HG-7-85-01 is a novel ATP-competitive and type II tyrosine kinase inhibitor targeting both wild-type and watchman mutant BCR-ABL, PDGFRα, Kit, and Src kinases, with inhibitory effects on the proliferation of a variety of cancer cell lines, leading to G0/G1-phase blockade and apoptosis induction in BCR-ABL-expressing cells.

JAK1:120 nM, BCR-ABL (T315I):3 nM, MK5:560 nM, RET:30 nM, KDR:20 nM, PDGFRα:440 nM

HG-7-85-01 (0-1 μM; 24 hours; BCR-ABL-, BCR-ABL-T315I-, Kit-T670I-, PDGFRα-T674M-, and PDGFRα-T674I-expressing cells) treatment leads to G0G1 arrest of BCR-ABL-expressing cells [1] . HG-7-85-01 (0-1 μM; 72 hours; BCR-ABL-, BCR-ABL-T315I-, Kit-T670I-, PDGFRα-T674M-, and PDGFRα-T674I-expressing cells) treatment also leads to induction of apoptosis of BCR-ABL-expressing cells [1] . HG-7-85-01 treatment potently and selectively inhibits the proliferation of 32D- and Ba/F3 cells expressing nonmutant BCR-ABL and the BCR-ABL-T315I gatekeeper mutant. HG-7-85-01 shows higher potency against nonmutant BCR-ABL and BCR-ABL-T315I (IC 50 = 0.06-0.14 μM) [1] . HG-7-85-01 inhibits BCR-ABL kinase activity in a concentration-dependent manner, suggesting selective targeting of the BCR-ABL kinase as the mechanism of action of HG-7-85-01 [1] . HG-7-85-01 potently inhibits the proliferation of Ba/F3 cells expressing the Kit-T670I gatekeeper mutation (Ba/F3- Kit-T670I) and Ba/F3 cells expressing TEL/PDGFRβ and no effect on parental Ba/F3 cells. HG-7-85-01 inhibits Kit, PDGFR phosphorylation in a concentration-dependent manner [1] . The PDGFRα-T674M and PDGFRα-T674I gatekeeper mutant variants are highly responsive to HG-7-85-01 and significant IL-3 rescue [1] . HG-7-85-01 inhibits the proliferation of Ba/F3 cells transformed with human c-Src (EC 50 = 190 nM), T338I Src (EC 50 = 290 nM), and T338M Src (EC 50 = 150 nM; chicken c-Src numbering). And potently inhibits the proliferation of exon 11 Kit mutant-expressing cells, exon 9 kit mutant-expressing cells are significantly less responsive [1] . Cell Cycle Analysis [1] Cell Line: BCR-ABL-, BCR-ABL-T315I-, Kit-T670I-, PDGFRα-T674M-, and PDGFRα-T674I-expressing cells Concentration: 0 μM, 0.01 μM, 0.1 μM and 1 μM Incubation Time: 24 hours Result: Led to G0G1 arrest of BCR-ABL-expressing cells. Apoptosis Analysis [1] Cell Line: BCR-ABL-, BCR-ABL-T315I-, Kit-T670I-, PDGFRα-T674M-, and PDGFRα-T674I-expressing cells Concentration: 0 μM, 0.01 μM, 0.1 μM and 1 μM Incubation Time: 72 hours Result: Led to induction of apoptosis of BCR-ABL-expressing cells.

HG-7-85-01 has limited oral bioavailability (BAV % F mouse = 5 %, rat = 19 %), a moderate half life (T 1/2 mouse =1.1 h rat = 5.8 hours), a relative low maximal serum concentration (C max mouse = 106 ng/mL at 10 mg/kg , rat = 292 ng/mL and 2 mg/kg ) and a relatively high clearance (Cl mouse = 23 ml/min/kg, rat = 13 ml/min/kg) [1] .