Current research focus

Finished projects 

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1) Discovery of potent first-in-class Aurora Kinase B (AKB) inhibitor and selective against FLT-3 and KIT for a better myelosuppression profile

Aurora Kinase B is frequently over-expressed in several cancers including breast, lung and colon cancers. Inhibitors of AKB arrest the cell-cycle and prevent cancer cells from undergoing cell division. AKB inhibitors also synergy with chemotherapy and some targeted therapy, while sensitizing certain cancer cells to radiotherapy. AZD1152 (Barasertib) is a very potent AKB inhibitor, which is currently in clinical trials. However, 70% of the patients in clinical trials reported myelosuppression upon it's administration. This is arising from the off-target effects of AKB. Barasertib also inhibits the tyrosine kinases involved in normal hematopoiesis leading to synthetic legal toxicity. Addressing this issue, I have designed, synthesized and evaluated a scaffold which inhibits selectively AKB against tyrosine kinases. The pharmacophore feature responsible for this selectivity was identified. The lead compound from this project has a sub-nanomolar potency against AKB and is >2000 fold selective against tyrosine kinases. It also shows cellular potency. Growth inhibition assay on MDA-MB-468, a Triple negative breast cancer (TNBC) cell line, shows a GI50 value of 107 nM. 

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U.S. Provisional Patent Application No.:  63/023,930

https://doi.org/10.1016/j.ejmech.2020.112589

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2) Structural characterization of the DFG flip of Aurora Kinase B using metadynamics to aid the discovery of 2nd generation AKB inhibitors

Despite the therapeutic potential of AKB in cancer, not many selective inhibitors of AKB are known. Small molecule kinase inhibitors which inhibit both the active state (type I inhibitors) or inactive state (type II inhibitors) are known, in addition to the allosteric and covalent inhibitors (type III-VI). However, inhibitors which bind to inactive conformation of AKB are not discovered yet. This could be arising from the lack of sufficient structural data on the inactive 'DFG-out' conformation, which is not yet crystallized. In this work, using enhanced sampling method of metadynamics, the DFG-out conformation of AKB was simulated from the experimentally determined active 'DFG-in' state. The structural changes in this transition were characterized with interesting insights into the possible intermediate states which also are potentially druggable.

PMID: 31853739

DOI: 10.1208/s12248-019-0399-6

 

3) Discovery of imidazopyridine-based compounds selectively inhibiting the growth of NIK- dependent cell lines in multiple myeloma

NF-kB pathway is important in proliferation, apoptosis and immune response, and is dysregulated in several cancers including multiple myeloma. Several drug discovery projects aimed at and successfully produced NIK inhibitors. However, they show non-specific inhibition of multiple myeloma cell lines. Further, they show poor enzymatic-cellular co-relation which challenges the idea of NIK of a cancer therapeutic target. Addressing this issue, we discovered a new scaffold which has increased cellular potency and selectively inhibits the NIK-dependent cell lines of the alternative NF-kB pathway. The target identification of these compounds is currently in progress.

 

 

 

 

 

 

 

 

 

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4) Pyrrolo[2,3-d]pyrimidine derivatives as inhibitors of RET: Design, synthesis and biological evaluation

• Small molecule inhibitors against RET-wt and RET V804M mutant were discovered

• The lead compound inhibits the proliferation of RET-fusion driven lung cancer cell line

• The lead compound also demonstrates ability to inhibit migration of cancer cells in in-vitro models

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DOI: 10.1016/j.ejmech.2020.112691