Design,Synthesis And Antitumor Activity Study Of 3,6 Two Substituted Indazole Drivatives As Type Ⅱ Kinase Inhibitor

Indazole ring is widely used in drug development due to its special chemical structure and biological characteristics.Axitinib is a type I kinase inhibitors approved by FDA for renal cancer that contain indazole ring s.Axitinib has inhibitory activities against multiple targets,such as VEGFR,c-kit and PDGFR.Studies have shown that Axitinib has certain inhibitory activity against BCR ABL T315I mutant kinase and c-kit T670I mutant kinase.Based on this,this thesis mainly around to overcome the current clinical CML and GISTs of drug resistant mutation,the key problems from the structure of the ash for Nepal,use of indazole ring for female nuclear design synthesis of the two series of new type Ⅱ kinase inhibitors against drug-resistant mutations,and the antitumor activity of related research.Pater 1:Discovery of CHMFL-ABL-121 as a highly potent ABL kinase inhibitor capable of overcoming a variety of ABL mutants including T315I for CMLThere is still a great demand for the drugs which can overcome a variety of imatinib resistant ABL mutants in the clinic.Starting from a type Ⅰ binging mode inhibitor axitinib,which has been reported to overcome ABL-T315I mutant induced resistance,through a structure guided drug design approach and binding mode switch strategy,a novel type Ⅱ ABL inhibitor CHMFL-ABL-121 have been discovered.Compound CHMFL-ABL-121 significantly improved the inhibitory activity against ABL wt and a broad spectrum of mutants including the most prevalent imatinib-resistant gatekeeper mutant T315I.It exhibited IC50 values of 2 nM and 0.2 nM against purified inactive ABL wt and T315I kinase protein respectively and inhibited the proliferation of the established CML cell lines with GI50 at single digit nM.In cellular context,CHMFL-ABL-121 strongly affected BCR-ABL mediated signaling pathways and induced apoptosis by arresting cell cycle into G0/G1 phase.In the in vivo study,50 mg/kg/day dosage of CHMFL-ABL-121 displayed TGI of 52%in the TEL-ABLT315I-BaF3 cell inoculated allograft mouse model without obvious toxicity.CHMFL-ABL-121 is highly sensitive to ABL T315I drug-resistant mutations at the protein level and cellular level,and its good in vivo anti-tumor effect makes it a potential candidate drug for CML,especially for patients with multiple imatini-resistant mutants.Pater 2:Discovery of CHMFL-KIT-033 as a Novel c-KIT T670I Mutant Selective Kinase Inhibitor for GISTsGain-of-function mutations of c-KIT kinase play crucial pathological roles for the GISTs.Despite of the success of imatinib as the first line treatment of GISTs,dozens of drug-acquired resistant mutations emerge and c-KIT T670I is one of the most common mutants among them.Although several kinase inhibitors are capable of overcoming the T670I mutant,none of them can achieve the selectivity over the c-KIT wt which also plays important roles in a variety of physiological functions such as hematopoiesis.Starting from axitinib,through fragments hybrid type II kinase inhibitor design approach,we have discovered a novel inhibitor CHMFL-KIT-033,which not only exhibits potent activity to c-KIT T670I mutant but also achieves 12-fold selectivity over c-KIT wt.Compound CHMFL-KIT-033 displays good antiproliferative effects against c-KIT T670I mutant driven GISTs cell lines(GIST-T1/T670I and GIST-5R),and also exhibits suitable in vivo PK profiles as well as dose-dependent antitumor efficacy.This study provides a proof-of-concept for developing c-KIT mutant selective inhibitor which theoretically could render better therapeutic window.