Iwao Ojima - US grants

The proposed research is aiming at i) developing new and effective methods for the asymmetric synthesis of beta-lactams and azetidines based on addition-cyclizations and cycloadditions: By means of the effective methods developed, a variety of chiral synthetic building blocks for peptide analogs, poly-beta-lactams, and polyazetidines will be synthesized: These new methods are also beneficial to the synthesis of beta-lactam antibiotics in general, ii) synthesizing "deoxo" analogs of brain peptides and labelled peptides for neurobiological studies using the "azetidine synthon method" and "beta-lactam synthon method": The behavior of new "deoxo" analogs of enkephalin and vasopressin toward enzymatic degradation in the brain will be studied: A new method for the stereo- and regiospecific labelling of peptides will be developed and established using a stereospecific cleavage of beta-lactam with tritium or deuterium, iii) synthesizing chiral cyclic poly-beta-lactams and polyazetidines as potential ionophores or reagents for endonucleolytic cleavage of DNA; metal ion binding ability of these chiral heterocyclic ligands will be investigated and several metal complexes will be synthesized, which are expected to intercalate into double-strand DNA and cleave it, and iv) biological study and biological activity screening in collaboration with a neurobiologist, a biochemist and the institutions which have excellent testing facilities.

This research on transition metals for homogeneous catalysis will be supported by the Organic and Macromolecular Chemistry Program. The development of new synthetic tools based on catalytic systems has the potential to provide more economic, pollution-free methods for the synthesis of the complex materials for industry and agriculture. The ultimate goal is to design and develop multi-functional multicatalyst systems which will permit multi-step synthesis in one-pot in a highly organized manner. This project includes three sub-projects: (i) mechanistic study of mixed metal catalyst systems focusing on the mechanism of CoRh(CO)7 catalysis including high pressure FT-IR study on the behavior of this unique mixed-metal complex regarding the hydroformylation-amido-carbonylation process; (ii) elucidation of the mechanism of amidocarbonylation by stereochemical approach which will resolve a historical mystery, i.e., water cleaves acylcobalt bond selectively in the presence of high pressure hydrogen, by designing bicyclic intermediates bearing strict steric requirements that can unambiguously distinguish among the possible mechanisms proposed; (iii) chelation-directed regio- and stereocontrol in carbonylations, which will systematically introduce chelation control, for the first time, to carbonylations and apply it to the catalytic asymmetric synthesis.

Our ultimate goal is to design and develop multi-functional multi- catalyst systems which enable us to carry out multi-step synthesis in one-pot in a highly organized manner. As a fundamental approach to this challenging goal, we will initiate and promote the research on the "new synthesis of biochemicals with homogeneous catalysts". This project includes four subprojects. (i) Elucidation of the mechanism of amidocarbonylation by stereochemical approach, in which we will solve a historical mystery, i.e., water cleaves acylcobalt bond selectively in the presence of high pressure hydrogen, by designing bicyclic intermediates bearing strict steric requirements so that we can unambiguously distinguish the possible mechanisms proposed. (ii) Chelation- directed regio- and stereocontrol in carbonylations, in which we will systematically introduce chelation control, for the first time, to carbonylations and apply it to the catalytic asymmetric synthesis. (iii) Applications of intramolecular amidocarbonylation' to the synthesis of nitrogen heterocycles, in which we will develop efficient new methods for the synthesis of biologically active nitrogen heterocyles, especially the intermediates for alkaloids. (iv) High pressure FT-IR study on the mechanism of CoRh(CO)7 catalysis in which the behavior of this unique mixed-metal cluster will be studied regarding the hydroformylation- amidocarbonylation process.

Our ultimate goal is to develop and establish new, efficient and reliable new methodologies for the synthesis of various non-protein amino acids and related compounds with perfect control of stereochemistry. Those methodologies are very beneficial for the investigation of the biological functions on non-protein amino acids and related compounds which cannot be obtained in sufficient quantity by isolation from natural sources. As a fundamental approach to this challenging goal, we will initiate and promote the research on the asymmetric synthesis of non-protein amino acids and related compounds by applying the "beta-Lactam Synthon Method" which has been developed in our laboratory. The proposed research has two projects. In the project (1), we will develop effective methods for the asymmetric synthesis of alpha-substituted alpha-amino acids and their dipeptides on the basis of highly stereoselective mono-, double-and triple alkylations of beta-lactam esters. A new cleavage methods via 4-hydroxymethyl-beta- lactams will be examined, and new ketenes and enolates with recyclable chiral auxiliaries will be developed. In the Project (2), we will explore new and efficient routes to a variety of non-protein amino acids and their derivatives through highly stereoselective functionalizations and transformations of enantiomerically pure 3-amino-4-alkenyl-beta-lactams. We will develop various new asymmetric organic transformations during the course of this project. Those non-protein amino acids and their derivatives, thus obtained, will furnish components of naturally occurring antibiotics and their analogues, plant metabolites, enzyme inhibitors, carbohydrates, and useful building blocks of peptide hormone analogues and chiral macrocycles. We will apply the new version of "beta-Lactam Synthon Method" to the asymmetric synthesis of (i) the ceramide of gangliosides which are important glycoshingolipids associated with membranes in the brain and vertebrate cells, and (ii) (R,S)- and (R,R)-3-chloro-4- hydroxyphenylserines which are important components of vancomycinic acid.

Stony Brook This research has two foci. First, the development of new carbocyclization reactions will be carried out by probing cascade tricyclizations, by trapping of the intermediates in silylcarbocyclization (SiCaC) reactions and by testing the scope of hetero-SiCaC reactions. Second, a synthetic and mechanistic study of homogeneous catalysis in supercritical carbon dioxide will be carried out. Both higher reaction rates and greater reaction selectivity are to be expected from this approach. With this renewal award, the Synthetic Organic Program and the Office of Multidiciplinary Activities are supporting the research of Dr. Iwao Ojima of the Department of Chemistry at the State University of New York, Stony Brook. Professor Ojima will focus his work on developing new and efficient homogeneous catalytic reactions incorporating carbocyclizations and carbonylations in conjunction with heterobimetallic catalyst systems. The methodology affords synthetic chemists powerful tools for the preparation of a large number of cyclic molecules.

DESCRIPTION: (Principal Investigator's Abstract) The ultimate goal of our research is to design and develop highly efficient catalytic processes for the syntheses of enantiopure biochemicals, which enable us to carry out multi-step synthesis from simple starting materials in a highly organized manner. These highly efficient and sophisticated catalytic processes, especially catalytic asymmetric transformations, may eventually replace many conventional methods for the syntheses of pharmaceuticals and other biologically active compounds of medicinal interest. As the continuation of our approaches to this challenging goal, we will focus our efforts on the development of new and efficient catalytic synthetic processes for the asymmetric synthesis of heterocyclic and carbocyclic compounds of medicinal interest in the next funding period. The proposed research includes the following two specific aims. 1. Development of new and efficient catalytic methods and catalytic asymmetric processes for the syntheses of heterocycles and carbocycles. In this project, we will perform extensive investigations on the development of new methodologies on catalytic annulation processes including regio-, stereo-, and enantioselective directed hydrosilylations, directed silylformylations, silylcarbocyclizations (SiCaCs), and cyclohydrocarbonylations for the synthesis of heterocycles and carbocycles. 2. Asymmetric synthesis of heterocyclic, carbocyclic, and related compounds of medicinal interest. In this project, we plan to develop new synthetic routes to a variety of enantiopure heterocyclic and carbocyclic compounds of medicinal interest featuring diastereoselective or enantioselective catalytic processes as the key steps.

The long-term objectives of this research program are (i) to explore and develop new and efficient methodologies for the syntheses of a variety of compounds of medicinal interest and (ii) to discover and develop new and effective anticancer agents as MDR reversal agents. This research program is very interdisciplinary and has been and will be carried out in collaboration with world-leading experts in each discipline. There are three specific aims: (1) Development of efficient methods for the synthesis of enantiopure non-protein amino acids, peptidomimetics and related compounds of medicinal interest. It is essential to develop and establish efficient and reliable new synthetic methodologies in order to attack important problems in medicinal chemistry and molecular medicine. As an approach to this challenging goal, the PI will further promote our very productive research on the asymmetric synthesis of non- protein amino acids, dipeptide isosteres and related compounds. New methods applicable to combinatorial chemistry will be developed. (2) Development of new generation taxoid antitumor agents (2.1.) Determination of bioactive conformation of paclitaxel. It is extremely important to find out how paclitaxel, a powerful anticancer drug, interact with microtubules in order to stabilize it and then to inhibit the cell division. The PI is very close to reveal the microtubule-bound conformation of paclitaxel for the first time using fluorine probe of paclitaxel by means of the solid state 19FNMR analysis as well as exciton chirality CD method. (2.2.) Design and synthesis of second and third generation taxoid antitumor agents. The PI will continue to develop the second generation taxoids based on the SAR study. The PI will find out the common pharmacophore of paclitaxel, epothilones, and discodermoride based on the information obtained in the specific aim (2.1.), SAR study, and molecular modeling. Once the common pharmacophore is defined, the PI will design the third generation taxoid antitumor agents that may not have taxane structure anymore. (2.3.) Studies on the photoaffinity labeling with, the metabolism of and macrophage activation by taxoids. The PI will perform photoaffinity labeling of microtubules and P-glycoprotein as well as the metabolic study of taxoids by P-450s using strategically fluorinated taxoids that can block specific oxidation sites. The PI will also look at the ability of taxoids to activate macrophages producing NO and/or TNFalpha. (3) Development of new MDR reversal agents from baccatins. Drug resistance in cancer chemotherapy is a serious problem. In order to solve this problem, the PI will continue his successful approach to the development of MDR reversal agents based on the strategic modification of baccatins.

*** 9709164 LE NOBLE This award from the Chemistry Research Instrumentation and Facilities (CRIF) Program will help the Department of Chemistry at the SUNY at Stony Brook to acquire a fluorescence spectrometer. This equipment will enhance research in a number of areas including the following: (1) binding and fluorescence quenching experiments to probe partially folded states of proteins, (2) the role of protein surface loops in the reaction catalyzed by the interfacial enzyme cholesterol oxidase, and (3) the mechanism of the enzymes enoyl-CoA hydratase and acyl-CoA dehydrogenase. The fluorescence spectrometer counts photons of light in the UV and visible regions and when a sample of material is illuminated by UV light, filtered to absorb the reflected UV light, then only visible fluorescence is detected. The spectrometer is used in fluorescence quenching experiments which occur at fast rates, and will allow relaxation processes to be used at various temperatures. ***

9726789 Ojima This award supports a three year collaborative research project between Professor Iwao Ojima of SUNY, Stony Brook, Professor Keiji Morokuma of Emory University and Professor Eiichi Nakamura of the University of Tokyo in Japan. The researchers will be undertaking experimental and theoretical studies on structure and catalytic activity of di- and polynuclear metal complexes. Professor Ojima has been designing and developing new and efficient homogeneous catalytic reactions promoted by heterobimetallic catalyst systems, that provide useful synthetic methods for organic synthesis. He has discovered silylformylation and various silylcarbocyclizations and has been trying to elucidate the most plausible mechanisms for these catalytic processes. His collaborations with theoretical chemists, who have experience in analyzing the problems in homogeneous catalysis and di-/polynuclear metal complex systems, will provide insight into the theoretically predicted pathways. This project brings together the efforts of three laboratories that have complementary expertise, research capabilities and equipment. Professor Ojima's expertise is in organometallic chemistry and homogeneous catalysis. Professor Morokuma is a theoretical chemist who can uniquely deal with the catalytic cycles of transition metal catalyzed processes. Professor Nakamura has a wide range of expertise in experimental as well as theoretical research. It is anticipated that this trilateral collaborative research will disclose novel mechanistic aspects of the catalysis of di- and polynuclear metal complexes, which are very likely to imply new organometallic species in the catalytic cycle. This information will stimulate the exploration of new and significant organometallic transformations and help in the design of highly regio-, stereo- and enantioselective catalyst systems with applications in industrial processes. Through the exchange of ideas and technology, this project will broaden o ur base of basic knowledge and promote international understanding and cooperation. ***

This award from the Chemistry Research Instrumentation and Facilities Program (CRIF) will assist the Department of Chemistry of SUNY at Stony Brook in acquiring a preparative ultracentrifuge. The areas of chemistry enhanced by the equipment include: (1) the design and characterization of new magnetic contrast agents for magnetic resonance imaging, (2) the synthesis of coenzyme A and palmitoyl-coenzyme A analogs, (3) the folding of the ribosomal protein L9 and of the E3/E1P domain, (4) the role of protein surface loops and hinges in the reactions catalyzed by triosephosphate isomerase and the interfacial enzyme cholesterol oxidase, (5) the binding site for fertilin-beta in its receptor, (6) the synthesis of polyfunctional organosilanes as inhibitors of aspartic and metalloproteases, (7) the study of the interfacial enzyme phospholipase D and (8) the spectroscopic analysis of the molecular forces leading to catalysis in the reactions catalyzed by enoyl-coenzyme A hydratase and enoyl-acp reductase. The instrument will also be used in two advanced undergraduate laboratories. Ultracentrifugation is a technique used mainly to aid in the isolation and purification of proteins. The capability of chemists to carry out cutting edge research in bioorganic chemistry demands access to state-of-the-art preparative ultracentrifuges.

This project addresses the development of new and efficient carbocyclization and higher order cycloaddition reactions, providing synthetic routes to appropriately functionalized polycyclic intermediates for the syntheses of bioactive natural and unnatural products. Novel fine-tunable monodentate phosphorus ligands and their applications to highly efficient catalytic asymmetric reactions and processes will also be explored. Particular attention will be placed on "green chemistry" concepts, including high selectivity and "atom economy" as well as the highly efficient separation and recovery of catalyst species, through the development of fluorous catalyst systems.

With this renewal award, the Organic and Macromolecular Chemistry Program is supporting the research of Dr. Iwao Ojima of the Department of Chemistry at the State University of New York at Stony Brook. One of the most fascinating goals in catalysis is to create effective catalyst systems that can promote multi-step reactions giving useful chemical substances, including those with multiple chiral centers, from simple starting materials. These catalyst systems should also promote the reactions with extremely high turnover frequency as well as turnover number and/or with highly efficient catalyst recovery and reuse without environmental concerns. Professor Ojima and his students are designing and developing new and efficient catalytic organic reactions incorporating (poly)cyclizations and carbonylations as key unit reactions, which provide useful synthetic methods for organic syntheses.

With this award from the Chemistry Research Instrumentation and Facilities (CRIF) Program, the Department of Chemistry at the State University of New York in Stony Brook will acquire a 400 MHz NMR Spectrometer. This equipment will enable researchers to carry out studies on a) the development of synthetic processes based on organometallic catalysts and the development of synthetic methods for natural products and their congeners (Ojima); b) synthesis of biologically active natural products and designed molecular probes (Parker); c) synthesis of analogues of Coenzyme A and development of computer-designed receptors and sensors for biological molecules (Drueckhammer); d) investigations on the role of disintegrins in mammalian fertilization and on understanding enzyme motion (Sampson); e) the structure and reactivity of all-carbon molecules (Goroff); and f) the preparation of designed supramolecular structures (Fowler).

Nuclear Magnetic Resonance (NMR) spectroscopy is the most powerful tool available to chemists for the elucidation of the structure of molecules. It is used to identify unknown substances, to characterize specific arrangements of atoms within molecules, and to study the dynamics of interactions between molecules in solution. Access to state-of-the-art NMR spectrometers is essential to chemists who are carrying out frontier research. The results from these NMR studies will have an impact in a number of areas including biochemistry, biological sensor development, and materials chemistry.

DESCRIPTION (provided by applicant): This proposal requests funds to create a drug discovery program in Madagascar that will provide economic benefits and contribute to biodiversity conservation in the bio-rich moist forests surrounding Ranomafana National Park in southeastern Madagascar. The Institute for the Conservation of Tropical Environments (ICTE), based at Stony Brook University, will build on its 17 years experience in Madagascar to negotiate agreements with Malagasy officials and local traditional leaders, obtain permits and assist with the logistics of working in Madagascar. ICTE manages a research station in Ranomafana that will be used as the local base of operation and also supply some chemical laboratory space. The University of Antananarivo in Madagascar will continue the pursuit of ethnobotanical drug discovery leads while the California Academy of Sciences will expand its bio-survey activities to include bioprospecting and supply novel materials for extraction. The Institute for Chemical Biology and Drug Discovery (ICB&DD) at Stony Brook will provide expertise in structure determination, structure-activity relationship studies, and selection of drug candidates. INDENA SPA., a private company dedicated to the commercial development of pharmaceutical, health-food, and cosmetic products, which has a base of operations near Ranomafana, will be responsible for bulk purification and the commercial development of pure compounds and/or extracts. Initial drug discovery activities will focus on a traditional cough remedy and plants that appear to contain anti-malarial ingredients. The ICBG will work with experts in strategic planning and business development to plan sustainable economic incentives related to these drug discovery activities. The Group is dedicated to training Malagasy people in all aspects of drug discovery and to using the best practices towards developing both sustainable and fair commercial use of the biodiversity-rich resources of the Ranomafana region.

[unreadable] DESCRIPTION (provided by applicant): The long-term objective of this research program is to discover and develop new and effective chemotherapeutic agents for fight against cancer, including cytotoxic agents, immunoconjugates, and multidrug resistance (MDR) reversal agents based on taxanes, taxoids and their congeners by combining new methodology in organic synthesis, medicinal chemistry, modern spectroscopic methods, chemical biology, and molecular pharmacology, connecting translational research to medical and clinical oncology. This research program is very interdisciplinary and has been and will be carried out in collaboration with world leading experts in each discipline. There are three specific aims: 1.1. Design and development of highly tumor specific taxoid-conjugates as new chemotherapeutic agents In general, widely used cytotoxic chemotherapeutic agents have serious drawbacks, i.e., these drugs cannot distinguish cancer cells from normal cells and this unfortunate feature constitutes major basis for a variety of undesirable side effects. In order to overcome these drawbacks, the PI will explore tumor activated prodrug strategy with the use of appropriate antibodies that recognize particular tumor surface antigens as well as special fatty acid that tumor cells seek for as vehicle for tumor-specific delivery of highly cytotoxic taxoid anticancer agents. 1.2. Development of taxane-based agents that can overcome drug-resistance in cancer The PI plans to undertake a systematic study on various drug-resistance in cancer and explore new approaches to overcoming this problem. This specific aim includes photoaffinity labeling of P-glycoprotein and development of new generation taxoid anticancer agents that are effective against drug-resistant tumors as well as highly effective taxane-MDR reversal agents (TRAs). 1.3. Design and development of de novo microtubule-stabilizing antitumor agents The PI will continue to investigate the microtubule-bound conformations of several microtubule-stabilizing anticancer agents and their common pharmacophore. Based on the tubulin-bound paclitaxel and taxoid structures, the PI will design and synthesize novel conformationally restricted taxoids as well as de novo antitumor agents that stabilize microtubules. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): It is evident that the widespread misuse of antimicrobial drugs has caused bacterial resistance to all classes of antibiotics. At present, one of the most serious problems worldwide is the multi-drug resistant tuberculosis (MDR-TB), which is classified as an emerging infectious disease threat and a category C priority pathogen by NIAID/NIH. In addition, the recent emergence of extensively drug resistant strains of TB (XDR-TB) that are resistant to both first and second line drugs is even more alarming. Another threat is the infections due to drug-resistant Enterococci (VRE) and Staphylococcus aureus (MRSA), which are serious problems in hospitalized or immunocompromised individuals. There has been a rapid increase in the incidence of VRE infections, as well as a dramatic increase in the incidence of MRSA infections. Unfortunately, at present, there are only very limited therapeutic options available for patients with these infections. Therefore, there is an urgent need for the development of novel antimicrobials against new targets essential for growth, whose inhibition should give a lethal phenotype. Thus, we have selected FtsZ, the tubulin homologue in bacterial cells and essential to bacterial cell division, as the specific target to develop a new class of antimicrobial agents. The bacterial tubulin homologue FtsZ is an essential cell-division protein in bacteria that polymerizes in a GTP-dependent manner, forming a cytokinetic ring at the septum site. Accordingly, FtsZ is a very promising target for discovery and development of new broad-spectrum antimicrobial drugs because of its central role in bacterial cell division. The Principal Investigator (PI) has expertise in anticancer agents targeting tubulin/microtubules and has hypothesized that a certain class of taxanes (microtubule-stabilizer) and benzimidazoles (tubulin polymerization inhibitors) should inhibit the depolymerization or polymerization of FtsZ from Mycobacterium tuberculosis (MTB), MRSA and VRE. The fact that the sequence homology between FtsZ and tubulin is low (<20% identity) strongly indicates an excellent possibility in discovering FtsZ-specific taxanes and benzimidazoles that are non-cytotoxic to human host cells. Building upon highly encouraging preliminary results, the following specific aims will be investigated: (1) Design, Synthesis, Screening and Optimization of Taxanes and Benzimidazoles (2) Investigation into the Mechanism of Action in vitro (3) Investigation into the Mechanism of Action in Live Cells (4) In vivo Efficacy Evaluation with Animal Models Highly integrated collaborative activities will be performed through close cooperation between the Institute for Chemical Biology and Drug Discovery (ICB&DD) at Stony Brook University and The Mycobacteriology Laboratory at Colorado State University. PUBLIC HEALTH RELEVANCE: Multi-drug resistant and extensively drug resistant tuberculosis (MDR-TB and XDR-TB) are classified as an emerging infectious disease threat and category C priority pathogens by NIAID/NIH. Another emerging threat is the infections due to drug-resistant Staphylococcus aureus (MRSA) and Enterococci (VRE), which are serious problems in hospitalized or immunocompromised individuals. Unfortunately, at present, there are only very limited therapeutic options available for patients with these infections. Therefore, there is an urgent need for the development of novel antimicrobials against new targets essential for growth, whose inhibition should give a lethal phenotype. Thus, we have selected FtsZ, the tubulin homologue in bacterial cells and essential to bacterial cell division, as the specific target to develop a new class of antimicrobial agents.

DESCRIPTION (provided by applicant): Cancer is the second major cause of death (the No. 1 cause of death for age 85 or younger population) in the U.S. Despite the significant progress in the development of cancer detection, prevention, surgery and therapy, there is still no common cure for patients with malignant diseases. In addition, the long-standing problem of chemotherapy is the lack of tumor-specific treatments. Traditional chemotherapy relies on the premise that rapidly proliferating cancer cells are more likely to be killed by a cytotoxic agent. In reality, however, cytotoxic agents have very little or no specificity, which leads to systemic toxicity, causing undesirable severe side effects such as hair loss, damages to liver, kidney and bone marrow. Therefore, various drug delivery protocols and systems have been explored in the last three decades. In general, a tumor-targeting drug delivery system consists of a tumor recognition moiety and a cytotoxic warhead connected directly or through a suitable linker to form a conjugate. The conjugate, which can be regarded as guided molecular missile, should be systemically non-toxic. This means that the linker must be stable in blood circulation. Upon internalization into the cancer cell the conjugate should be readily cleaved to regenerate the active cytotoxic warhead. A rapidly growing tumor requires various nutrients and vitamins. Therefore, tumor cells overexpress many tumor-specific receptors, which can be used as targets to deliver cytotoxic agents into tumors. We have successfully targeted tumor xenografts in animal models by employing monoclonal antibodies and polyunsaturated fatty acids. In the next funding period, we plan to use vitamins (biotin and folic acid), hyaluronic acids and aptamers as the guiding modules to construct guided molecular missiles for tumor- targeting chemotherapy. We will use mechanism-based linkers that are stable in blood circulation, but readily cleavable inside tumor cells. As the vehicle or platform for the novel tumor-targeting agents bearing multiple guiding modules as well as warheads, we will explore the high potentials of single-walled carbon nanotubes (SWNTs), ultra-short SWNTs and dendrimers, as well as drug conjugates with small-molecule splitter modules. Drug conjugates with dual targeting modules and/or dual warheads will also be studied. Imaging of the tumor-targeting process and drug release in vitro and in vivo will be investigated by means of confocal fluorescence microscopy, MRI and PET. For that purpose, drug conjugates with ultra-short SWNTs encapsulating gadolinium ions as well as [11C]-labeled warheads will be synthesized. PUBLIC HEALTH RELEVANCE: Statement One of the long-standing problems of chemotherapy is the lack of tumor-specific treatments, i.e., traditional chemotherapy relies on the premise that rapidly proliferating cancer cells are more likely to be killed by a cytotoxic agent. In reality, however, cytotoxic agents have very little or no specificity, which leads to systemic toxicity, causing undesirable severe side effects. Therefore, the development of new and efficient tumor-specific drug delivery systems with potent anticancer agents is an urgent need in the 21st century chemotherapy to dramatically enhance the efficacy and eliminate undesirable side effects. This proposal deals with novel tumor-targeting drug delivery systems to address these urgent medical issues.

Project Summary Despite advances in anti-androgen and taxane-based therapies, prostate cancer (PC) often becomes castration-resistant, metastatic, and incurable. Consequently, there is an urgent need to develop novel interventions to treat metastatic PC. Lipid signaling and metabolism are major drivers of PC metastasis and present ideal targets for therapeutic intervention. However, therapeutic exploitation of lipid signaling systems is hampered by the existence of multiple lipid metabolizing enzymes and nuclear receptors, which would necessitate targeting these systems in parallel. Fatty acid binding protein 5 (FABP5) is an intracellular carrier that shuttles bioactive lipids to nuclear receptors, thereby activating gene transcription programs that enhance tumor growth and metastasis. FABP5 is not expressed in the normal prostate but becomes highly upregulated in advanced metastatic PC. Our group has obtained preliminary data demonstrating that FABP5 is indispensable for the delivery of pro-tumorigenic lipids produced by multiple cytosolic to nuclear receptors to promote PC metastasis. This positions FABP5 as an essential node in a PC lipid signaling network and an attractive target for the development of therapeutics to treat metastatic PC. Despite the considerable promise of FABP5 inhibitors as potential PC therapeutics, potent and selective inhibitors have yet to emerge. The major goal of this proposal is to develop and optimize novel potent and selective FABP5 inhibitors. The proposed multidisciplinary project will be carried out by a highly qualified team with expertise in computer-aided drug design, medicinal chemistry, and PC biology. Aim 1 will leverage structure-based drug design and iterative chemical synthesis approaches to identify and optimize FABP5 inhibitors for potency and selectivity. Aim 2 will employ a robust in vitro inhibitor testing platform including assessments of inhibitor potency, efficacy, selectivity, stability, and cytotoxicity in PC cell-lines and non-transformed cells. Aim 3 will assess the efficacy of candidate inhibitors in mouse models of PC, including a novel genetically engineered mouse model of androgen-dependent and castration-resistant PC. We will also assess the efficacy of FABP5 inhibitors when used as monotherapies and in combination with FDA approved therapeutics. Successful completion of the proposed studies will lead to the development of optimized FABP5 inhibitor scaffolds that can be advanced to late stage IND-enabling studies and eventual clinical deployment.