Chronic myeloid leukemia (CML), a hematological cancer of bone marrow white blood cells, constitutes about 15% of adult leukemia and usually 1-2 patient is diagnosed with CML per 100,000 people/per year in US. It is characterized by a reciprocal chromosomal translocation between chromosome 9 and 22 of the break point cluster region (BCR) gene with the Abelson (ABL) gene for ABL kinase, which leads to a shortened chromosome 22. The fusion tyrosine kinase BCR-ABL is constitutively active and leads to uncontrolled myeloid cell proliferation through downstream mediators such as Stat5 and ERK.

Despite of the great clinical success, the FDA approved that targeting BCR-ABL kinase for the CML drugs all potently inhibit other targets such as DDR1/2, c-KIT and so on besides ABL kinase. Although the role of off-targets inhibition is not very clear in the clinical aspect, the highly selective BCR-ABL inhibitor is still highly demanded from both the preclinical pathological and clinical side effects mechanistic study point of view.

Based on the X-ray structure of ABL kinase, the team designed the new generation highly potent and relatively selective BCR-ABL kinase inhibitor, CHMFL-ABL-053. The CHMFL-ABL-053 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 auto-phosphorylation (EC50 about 100 nM) and downstream mediators such as STAT5, Crkl and ERK’s phosphorylation, CHMFL-ABL-053 inhibited the proliferation of CML cell lines K562 (GI50 = 14 nM), KU812 (GI50 = 25 nM) and MEG-01 (GI50 = 16 nM). Pharmacokinetic study revealed that 18a had over 4 hours half-life and 24% bioavailability in rats. 50mg/kg/day dosage treatment could almost completely suppress the tumor progression in the K562 cells inoculated xenograft mouse model. As a potential useful drug candidate for CML, CHMFL-ABL-053 is under extensive preclinical safety evaluation now.

 

The results were published in ACS Journal of Medicinal Chemistry (DOI: 10.1021/acs.jmedchem.5b01618), entitled “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”.

This research was supported by the Scientific Research Grant of Hefei Science Center of CAS, the grant of “Cross-disciplinary Collaborative Teams Program for Science, Technology and Innovation ” from Chinese Academy of Sciences, Anhui Province Natural Science Foundation Annual Key Program, China “Thousand Talent Program” , “Hundred Talent Program” of the Chinese Academy of Sciences and the National Natural Science Foundation of China.

CHMFL-ABL-053 anti-tumor efficacy in K562 xenograft model