Discovery And Pharmacological Studies Of Kinase Inhibitors For B-Cell Lymphoma

BTK(Bruton's tyrosine kinase)is a non-receptor tyrosine kinase which is subordinate to the TEC kinase family.It is mainly expressed in B cells,widely distributed in the lymphatic system,hematopoietic system and blood system.BTK plays an important role in the BCR signaling pathway.Studies has shown that abnormal expression of BTK is closely related to B cell lymphoma.Although there are some BTK inhibitors that have been studied in the pre-clinically model or clinically trials,most of the inhibitors do not just inhibit BTK,which targets other kinases similar to BTK,such as BMX,JAK3 or EGFR.And the inhibition of these kinases in the clinical easy to cause such as nausea,vomiting and other adverse reactions.And in the clinical trials the off-target cause some adverse reactions such as nausea,vomiting.Through a structure-based drug design approach,we discovered a highly potent(IC50:7 nM)irreversible BTK inhibitor compound 9(CHMFL-BTK-01),which displayed a high selectivity profile in KINOMEscan(S score(35)1/4 0.00)among 468 kinases/mutants at the concentration of 1 mM.Compound 9 completely abolished BMX,JAK3 and EGFR's activity.Both X-ray crystal structure and cysteine-serine mutation mediated rescue experiment confirmed 9's irreversible binding mode.9 also potently inhibited BTK Y223 auto-phosphorylation(EC50:<30 nM),arrested cell cycle in G0/G1 phase and induced apoptosis in U2932 and Pfeiffer cells.This paper mainly studies in the two aspects:1.Discovery CHMFL-BTK-01(compound 9)as a highly selective irreversible BTK inhibitor2.Pharmacology and Pharmacokinetics of CHMFL-BTK-01 We believe these features would make CHMFL-BTK-01 a good pharmacological tool to study the BTK related pathology.