HG-7-85-01 is a type II ATP competitive inhibitor of wild-type and gatekeeper mutations forms of Bcr-Abl, PDGFRα, Kit, and Src kinases. HG-7-85-01 inhibits T315I mutant Bcr-Abl kinase, KDR and RET with IC50 s of 3 nM, 20 nM and 30 nM, and is only weak or no inhibition of other kinases (IC50 >2 μM). HG-7-85-01 inhibits the cell proliferation, which is mediated by the induction of apoptosis, and inhibition of cell-cycle progression [1].
In Vivo, HG-7-85-01 has limited oral bioavailability (BAV % F mouse = 5 %, rat = 19 %), a moderate half life (T1/2 mouse =1.1 h rat = 5.8 hours), a relative low maximal serum concentration (Cmax 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].
In Vitro, 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 (IC50 = 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 (EC50 = 190 nM), T338I Src (EC50 = 290 nM), and T338M Src (EC50 = 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].
References:
[1]. Ellen Weisberg, et al. Discovery of a Small-Molecule Type II Inhibitor of Wild-Type and Gatekeeper Mutants of BCR-ABL, PDGFRalpha, Kit, and Src Kinases: Novel Type II Inhibitor of Gatekeeper Mutants. Blood. 2010 May 27;115(21):4206-16.
In Vivo, HG-7-85-01 has limited oral bioavailability (BAV % F mouse = 5 %, rat = 19 %), a moderate half life (T1/2 mouse =1.1 h rat = 5.8 hours), a relative low maximal serum concentration (Cmax 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].
In Vitro, 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 (IC50 = 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 (EC50 = 190 nM), T338I Src (EC50 = 290 nM), and T338M Src (EC50 = 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].
References:
[1]. Ellen Weisberg, et al. Discovery of a Small-Molecule Type II Inhibitor of Wild-Type and Gatekeeper Mutants of BCR-ABL, PDGFRalpha, Kit, and Src Kinases: Novel Type II Inhibitor of Gatekeeper Mutants. Blood. 2010 May 27;115(21):4206-16.