The drug resistance develops as a result of spontaneous genetic aberrations in the drug’s therapeutic targets or signaling pathways.
The most serious examples of acquired drug resistance involve the point of mutations of gatekeeper residues in the ATP-binding pocket of kinases. In spite of availability of oncology drugs for helping cancer patients harboring gatekeeper mutations, these drugs do not have enough therapeutic window, having issues either uncontrollable toxicity issues or mild efficacy.
Magicbullet therapeutic leadership team has well-positioned in kinase inhibitor development and accomplishment in license out deals including 4th generation of EGFR, mtNRAS, mtFlt3 inhibitors. Utilizing chemical screening campaign, our group previously identified small molecule kininase inhibitor, GNF-7 that could be serve as novel therapeutic targets in acute myeloid leukemias (AML) with G12D NRAS mutation (Blood, 2015, 3133-3143). ACK1/GCK dual inhibitor is the pre-clinical stage program, indication of colorectal cancer (CRC) and metastatic castration resistant prostate cancer (mCRPC), for targeting mtRAS that is the one of the most frequently mutated oncogenic drivers in human cancer. Our approach to overcome mtRAS is to develop indirect RAS signal pathway blocker that is able to block the downstream pathway of Pi3K and MAPK simultaneously by ACK1 and GCK.
Lastly, we are also actively progressing on 3rd generation reversible FGFR inhibitor to overcome an acquired resistant of gatekeeper mutants and our lead compound, MBT-K201, showed an excellent down signal inhibition of FGFR gatekeeper mutant, significantly improved potency compared to futibatinib, second generation of covalent inhibitor drug.