Discovery of 2-((3-Amino-4-methylphenyl)amino)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(methylamino)pyrimidine-5-carboxamide (CHMFL-ABL-053) as a Potent, Selective, and Orally Available BCR-ABL/SRC/p38 Kinase Inhibitor for Chronic Myeloid Leukemia

Journal of Medicinal Chemistry
Xiaofei LiangJing Liu

Abstract

Starting from a dihydropyrimidopyrimidine core scaffold based compound 27 (GNF-7), we discovered a highly potent (ABL1: IC50 of 70 nM) and selective (S score (1) = 0.02) BCR-ABL inhibitor 18a (CHMFL-ABL-053). Compound 18a did not exhibit apparent inhibitory activity against c-KIT kinase, which is the common target of currently clinically used BCR-ABL inhibitors. Through significant suppression of the BCR-ABL autophosphorylation (EC50 about 100 nM) and downstream mediators such as STAT5, Crkl, and ERK's phosphorylation, 18a inhibited the proliferation of CML cell lines K562 (GI50 = 14 nM), KU812 (GI50 = 25 nM), and MEG-01 (GI50 = 16 nM). A pharmacokinetic study revealed that 18a had over 4 h of half-life and 24% bioavailability in rats. A 50 mg/kg/day dosage treatment could almost completely suppress tumor progression in the K562 cells inoculated xenograft mouse model. As a potential useful drug candidate for CML, 18a is under extensive preclinical safety evaluation now.

References

Nov 2, 2001·Journal of Medicinal Chemistry·D H BoschelliF Boschelli
Jul 17, 2004·Science·Neil P ShahCharles L Sawyers
Feb 16, 2005·Cancer Cell·Ellen WeisbergJames D Griffin
Sep 24, 2005·Leukemia·G MartinelliM Baccarani
Dec 20, 2007·Molecular Cancer Therapeutics·Patrizia CarpinelliJürgen Moll
Feb 25, 2009·BMC Structural Biology·Jonathan A WingerJohn Kuriyan
Apr 29, 2009·Journal of Computational Chemistry·Garrett M MorrisArthur J Olson
Jan 15, 2010·Nature·Jianming ZhangNathanael S Gray
Jul 8, 2010·Journal of Medicinal Chemistry·Hwan Geun ChoiTaebo Sim
Jan 1, 2008·CSH Protocols·Andrew H FischerRolf Zeller
Jul 12, 2013·Nature Reviews. Cancer·Emileigh K GreuberAnn Marie Pendergast
Apr 23, 2014·Organic & Biomolecular Chemistry·Pathi Suman, Bhimapaka China Raju
May 17, 2014·Apoptosis : an International Journal on Programmed Cell Death·Yaqiong DongChengrong Lu

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