Discovery Of Selective TRK And MTOR Inhibitors

Part 1:The tropomyosin receptor kinase(TRK)is a class of nerve growth factor-activated receptor tyrosine kinase and is involved in regulation of many important physiological and pathological processes in living organisms.Biological studies show TRK is not only a key regulator in normal cell development,but also plays a key role in the occurrence and development of a variety of cancers.At present,small molecule TRK inhibitors,as a new type of cancer treatment drug,have significant therapeutic effects on TRK gene fusion cancer patients.However,due to resistance caused by kinase mutations,TRK inhibitors need to be more potent,higher selective,and more effective against mutations for clinical treatment.Based on our previous work,we found that CHMFL-ABL-121(17)showed good TRK activity in BaF3 cell line.Based on the crystal model of TRK,we designed and synthesized a series of indazole derivatives,through type Ⅱ inhibitor design approaches.IHMT-TRK-284(45)is a potent and selective type Ⅱ TRK inhibitor.Compound 45 exhibits strong TRK inhibit activity and displays a high selectivity profile(S score(1)=0.02)against the 468 kinase/mutants.More importantly,45 can overcome drug resistance mutations including V573M and F589L in the ATP binding pocket as well as G667C/S in the DFG region.At the same time,its good pharmacokinetics and efficacy data in vivo indicate that 45 might be a new potential therapeutic candidate for clinical treatment.Part 2:The mammalian target of rapamycin(mTOR)is a type of serine/threonine protein kinase in mediated downstream of TRK,and is also an important signal regulator in vivo.The natural product Lymphostin(63)is a small molecule inhibitor of mTOR(IC50=1.8 nM).Although Lymphostin has been extracted and identified for a long time,the research is limited to kinase profiling assay,and its mechanism with protein kinases have not been reported due to limited quantities.Based on the crystal structure of mTOR,our team found that Lymphostin may form a covalent bond with the sulfhydryl group in Cys2243 of mTOR through α,β-unsaturated ketones,thereby overcoming the drug resistance problem of mTOR inhibitors in the treatment of tumors.Therefore,our team continuously explored and optimized the conditions of the synthesis route of Lymphostin by using the method of organic synthesis and ethyl levulinate as raw material.At present,the route has been explored to the 13 th step,which has less steps and relatively higher yield compared with the reported route.It is expected that sufficient amount of Lymphostin will be synthesized by this route for further biological mechanism research.