Discovery Of Novel Type ? Kinase Inhibitors For Class ? Tyrosine Kinases

Type ? receptor tyrosine kinases,include PDGFRa,PDGFRp,CSF-1R,KIT and FLT3,which are performed as homodimers or heterodimers features.Type ? receptor tyrosine kinases play an important role in cancers such as acute myeloid leukemia,chronic eosinophilic leukemia,pulmonary hypertension,gastrointestinal stromal tumors,melanoma,etc.,which are also therapeutic targets and hot kinases.Most FDA-approved small molecules with type ? receptor tyrosine kinase activity are multi-target inhibitors,and many inhibitors cannot overcome wide-spectrum mutations.Using type ? fragment hybride approach we designed and synthesized four type ? kinase inhibitors,which are high selective or potent over a broad spectrum of drug resistant mutants.We report a new compound CHMFL-FLT3-335,which displays GI50 values of 30-80 nM against different ITD mutants and achieves selectivity over both FLT3 wt(8-fold)and cKIT kinase in the transformed BaF3 cells(>300-fold).CHMFL-FLT3-335 potently inhibits the proliferation of the FLT3-ITD-positive acute myeloid leukemia cancer lines through suppression of the phosphorylation of FLT3 kinase and downstream signaling pathways,induction of apoptosis,and arresting the cell cycle into the G0/G1 phase.CHMFL-FLT3-335 also displays potent antiproliferative effect against FLT3-ITD-positive patient primary cells.In the in vivo studies,CHMFL-FLT3-335 was demonstrated favorable PK profiles and suppressed the tumor growth in the MV4-11 cell inoculated mouse xenograft model.We report a new compound CHMFL-FLT3-362,which displays GI50 values of 30-80 nM against different ITD mutants and achieves selectivity over both FLT3 wt(10-fold)and cKIT kinase in the transformed BaF3 cells(>300-fold).It also displays impressive in vitro and in vivo efficacy against preclinical models of FLT3-ITD-positive AML.Our results show that CHMFL-FLT3-362 is a valuable research tool for FLT3 kinase related pathological study as well as a novel potential therapeutic candidate for FLT3-ITD+AML.Through a fragment hybrid type ? kinase inhibitor design approach,we discovered a novel c-KIT kinase inhibitor CHMFL-KIT-64,which is potent against c-KIT wt and a broad spectrum of drug resistant mutants.CHMFL-KIT-64 exhibits good in vivo PK profile in different species.It also displays good in vivo antitumor efficacy in the c-KIT T670I,D820G and Y823D mutants mediated mice models as well as in the c-KIT wt patient primary cells which are known to be imatinib-resistant.The potent activity against a broad spectrum of clinically important c-KIT mutants combining the good in vivo PK/PD properties of CHMFL-KIT-64 indicate that it might be a new potential therapeutic candidate for cKIT wt/mut driven GISTs and AML.Through type ? kinase inhibitors design approach,we discovered a new type ?selevtive PDGFR kinase inhibitor CHMFL-PDGFR-401,which selectively inhibits PDGFRa and PDGFR? but with no activities of cKIT,FLT3 or BCR-ABL.In vivo studies showed that CHMFL-PDGFR-401 was demonstrated favorable PK profiles and was suitable for oral administration,Cmax and F%were 3659 ng/mL and 92%respectively.CHMFL-PDGFR-401 was able to suppress the tumor growth in the EOL-1 cell inoculated mouse xenograft model and the tumor growth inhibition rate was over 90%at 100 mg/kg/d.