The goal of this project titled ?Developing chemical probes for oncogenic signaling pathways? is to promote identification of small molecules/chemical probes for cancer targets to elucidate underlying molecular mechanisms driving cancer and drug discovery efforts at the Moffitt Cancer Center (MCC). My Unit Director Dr. Said Sebti, is the Program Leader of the Chemical Biology Molecular Medicine (CBMM) program and Chair of the Drug Discovery Department, and recently awarded an R35 outstanding investigator award. I have demonstrated success in several medicinal chemistry projects in collaboration with Principal Investigators, and the 5 projects described in this application are funded via NCI. These projects will involve development of: 1. ACK1, 2. Mutant KRas, 3. Dual Aurora A /JAK2 inhibitors 4. Chemical probes to understand the mechanism of action of targeted drugs, and 5. Bifunctional molecules to target protein degradation. The synthetic chemistry strategies/approaches described in my proposal are expected to generate novel compounds to address significant challenges in several types of human cancers. The synthesis and validation of bifunctional molecules as PROTACs in kinase projects (ACK1, Aurora A-JAK2) is expected to advance the field/help to define tractable targets for this approach and provide new cancer therapies. As part of this award, I will continue to provide the Moffitt research community with critical enabling chemical biology support. This will include: structure based design and synthesis of focused libraries (hit-to-lead-optimization) to identify new compounds/chemical probes to explore the molecular mechanisms of proteins involved in cancer; scale-up synthesis and formulation of potent compounds (e.g. prodrug/salt formation, solvent/excipient optimization) for in-vivo studies; design/synthesis of chemical probes for affinity-based proteomics. In addition to the projects described here, I have several other medicinal chemistry collaborations with Cancer Center members that will lead to new directions in cancer therapy and I am in a unique position to integrate projects from the CBMM and Immunology programs. My contribution via synthesis of compounds was essential for peer reviewed publications and grant applications. Some of the major findings enabled by my contributions over the past 5 years include: (i) synthesis and development of Aurora A-JAK2 inhibitors and their application in GVHD; (ii) identification of novel, potent ACK1 inhibitors; (iii) synthesis of chemical probes for assessing target specificity of in-clinic tyrosine kinase and PARP inhibitors; (iv) synthesis/development of dual BRD4-kinase inhibitors, and (v) development of novel non- covalent proteasome inhibitors. I strongly believe the research projects described in this application will facilitate new directions, approaches, new chemical probes and drugs to study and target cancer, and I will devote 70% of my efforts (8.4 calendar months) to this award.
The proposed research in this application is relevant to public health and supports the NIH?s mission because the results from the studies will make a major contribution to our understanding of the mechanisms of proteins involved in oncogenic cell signaling pathways. It will also reveal previously unrecognized opportunities for the clinical development of advanced drug candidates. Identifying novel approaches and chemical probes/compounds as novel drugs is likely to produce personalized targeted therapies and significant survival benefits for a greatly underserved patient population.
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|Phadke, Manali; Remsing Rix, Lily L; Smalley, Inna et al. (2018) Dabrafenib inhibits the growth of BRAF-WT cancers through CDK16 and NEK9 inhibition. Mol Oncol 12:74-88|
|Kazi, Aslamuzzaman; Xiang, Shengyan; Yang, Hua et al. (2018) GSK3 suppression upregulates ?-catenin and c-Myc to abrogate KRas-dependent tumors. Nat Commun 9:5154|
|Akuffo, Afua A; Alontaga, Aileen Y; Metcalf, Rainer et al. (2018) Ligand-mediated protein degradation reveals functional conservation among sequence variants of the CUL4-type E3 ligase substrate receptor cereblon. J Biol Chem 293:6187-6200|