Monday, February 8, 2016

CHMFL-ABL-053 | Treatment for Chronic Myeloid Leukemia | ABL Inhibitor | Multi-Kinase Inhibitor

CHMFL-ABL-053 [2-((3-Amino-4-methylphenyl)amino)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(methylamino)pyrimidine-5-carboxamide] is an orally available, small molecule multi-kinase inhibitor for BCR-ABL,SRC and p38 kinases. Invitrogen SelectScreen biochemical assay revealed that CHMFL-ABL-053 exhibited an IC50 of 70 nM against ABL1 kinase and also strongly inhibited p38α (IC50 = 62 nM) and SRC kinases (IC50 = 90 nM). In addition, CHMFL-ABL-053  did not exhibit apparent potency against c-KIT kinase (IC50 = over 10000 nM), which is the common off-target for clinically used BCR-ABL inhibitors Imatinib, Nilotinib, Bosutinib, and Dasatinib. Moreover, it exhibited better selectivity against DDR1/2 kinases [1, 2].
CHMFL-ABL-053: 2D and 3D Structure

CHMFL-ABL-053 exhibited potent antiproliferation efficacies against all of the three BCR-ABL driven CML cell lines K562 (GI50 = 14 nM), KU812 (GI50 = 25 nM), and MEG-01 (GI50 = 16 nM) but not other AML cell lines, implying strong and selective on-target effects. In addition, CHMFL-ABL-053 did not display any apparent activity against the CHL cell line, indicating a good nonspecific toxicity profile.
In a K562 cell inoculated xenograft mouse model, 16 days of continuous treatment of CHMFL-ABL-053 dose-dependently inhibited the growth of the K562 tumor, and a 50 mg/kg/ day dosage could almost completely suppress tumor progression.

As a potential useful drug candidate for Chronic myeloid leukemia (CML), CHMFL-ABL-053  is under extensive preclinical safety evaluation now. CHMFL-ABL-053 is developed via joint efforts of Chinese Academy of Sciences and Hefei Institute of Physical Science, China [1].


Common name: CHMFL-ABL-053; CHMFL-ABL053; CHMFL-ABL 053
Molecular Formula: C28H26F3N7O2
CAS Registry Number: 1808287-83-3
CAS Name: 2-((3-Amino-4-methylphenyl)amino)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(methylamino)pyrimidine-5-carboxamide
Molecular Weight: 549.21
InChI: InChI=1S/C28H26F3N7O2/c1-15-7-9-19(12-22(15)32)36-27-34-14-21(24(33-3)38-27)26(40)37-23-13-20(10-8-16(23)2)35-25(39)17-5-4-6-18(11-17)28(29,30)31/h4-14H,32H2,1-3H3,(H,35,39)(H,37,40)(H2,33,34,36,38)
Activity: Treatment of CML; Treatment of Chronic Myeloid Leukemia; Anti-neoplastics Drug
Status: Pre-Clinical
Originator: Chinese Academy of Sciences and Hefei Institute of Physical Science

CHMFL-ABL-053 Synthesis

CN104876879A: This is the first disclosed synthesis. Also, see Ref. 2.

Step 1: Intermediate synthesis

Step 2: Final synthesis


1H NMR (Estimated) for CHMFL-AABL-053

1. Jing, L.; et. al. A novel bcr-abl kinase inhibitor. CN104876879A
2. Liang, X.; et. al. 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. J Med Chem 2016