Contributions to Science and Technology Development

Actively involved in the discovery of novel Cancer Stemness Inhibitors for Triple-Negative Breast Cancer (TNBC) treatment, for which treatment options are scarce. It is the most dreadful cancer in Indian women where 50% patients do not respond to treatment at all. Cancer stem cells (CSCs) are the root cause of chemoresistance and treatment failure. Eradicating CSCs will prevent relapse and cure cancer. This is latest thought process in anticancer drug discovery. The most advanced molecule – napabucasin is currently in Phase III trials for treatment of various tumors.

In collaboration with Godavari Biorefineries Ltd. (GBL), Mumbai, discovered first-in-class Cancer Stemness Inhibitor – MSP008-22 (IN201621035967, WO2018193476A2, US11084843, EP3612172A2, JP2020519568A). In March 2021, Investigational New Drug (IND) application submitted to CDSCO was approved. The Phase I clinical trials of MSP008-22 will begin in TNBC patients in October 2022. The clinical candidate was conceptualized and discovered by the applicant. It underwent extensive in vitro anticancer, anti-CSC as well as early-ADME/T, animal efficacy and preclinical safety pharmacology and toxicity studies over last 2½ years. Phase I studies will investigate the pharmacokinetics and tolerability of orally-administered MSP008-22, following first-in-human dosing. MSP008-22 is safe (rats, mice and dogs - maximum tolerated dose >1000 mg/kg), orally bioavailable, and efficacious either alone or in combination with leading anticancer agents.

The target identification studies of MSP008-22 led to the identification of a novel target. Further biophysical and molecular biology studies are in progress. Several Back-up molecules of MSP008-22 have been identified and are being profiled in several in vitro cell-based and physicochemical property assays (IN201821047582, WO2020129082A1, CN113365615, EP3897592). These back-up molecules will progress along the same path as MSP008-22.

In collaboration with GBL, Identified SARS-CoV-2 viral entry inhibitor, which demonstrated superior in vitro and in vivo efficacy in Golden Syrian Hamsters. The molecule has got approved Investigational New Drug (IND) status with permission to conduct Phase I studies in COVID-19 patients for the treatment and prevention perspectives (IN202021019866, PCT/IN2021/050451).

Actively working for the discovery of more potent Cancer Stemness Inhibitors to widen the therapeutic utility of these agents for a large number of solid and haematologic tumors (IN202021046675). Few very interesting NCEs with subnanomolar potency have already identified as Cancer Stemness Inhibitors. Consistent efforts from the applicant’s group will definitely lead to the discovery of potent Cancer Stemness Inhibitors for the treatment of several difficult-to-treat cancers. The next target is Glioblastoma multiforme (GBM) (Grade IV astrocytoma), very aggressive brain cancer.

Prof. Kharkar's PhD students worked extensively on the discovery of novel Cancer Stemness Inhibitors (DOI: 10.1002/ddr.21628 and 10.1002/ddr.21723). The identified hits were among the most potent anti-CSC agents discovered so far. These hits are currently in ‘Biological Testing’ phase and are marching towards ‘Lead Discovery and Lead Optimization’ stages. In addition, Prof. Kharkar’s previous work on anticancer drug discovery and development targeting human inosine 5’-monophosphate dehydrogenase 2 (hIMPDH2) led to the identification of several potent inhibitors of breast, prostate cancers and GBM (DOI: 10.1002/ddr.21557; 10.1016/j.ejmech.2018.09.016; 10.1080/14756366.2018. 1474211; 10.1055/s-0043-118538; 10.1016/-j.semcancer.2019.09.012; 10.1016/j.lfs.2017.07.015; 10. 1016/j.ejmech.2017.02.062; 10.1016/j.ejmech.-2017.02.022; 10.1007/s10495-015-1159-4). In an attempt to target H-Ras, Prof. Kharkar’s group discovered interesting chemical series starting from scratch using computer-aided molecular design (10.1002/jcb.27836). They also discovered potent dual inhibitors of transporter proteins ABCB1 (P-gp) and ABCG2 (BCRP) for the first time for dealing with multidrug resistance (MDR) problem in cancer treatment (10.1016/j.ejmech.2018.12.019). Prof. Kharkar and his collaborator’s group also devised nanotherapeutic delivery system for arsenic trioxide, a potent anticancer agent (10.1039/C7NR09503A).