Thursday, April 9, 2015

Drugs in Clinical Pipeline: BMS-599626

BMS-599626 [(S)-morpholin-3-ylmethyl(4-((1-(3-fluorobenzyl)-1H-indazol-5-yl)amino)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl) carbamate], a orally bioavailable small-molecule inhibitor of the human epidermal growth factor receptor (HER) kinase family, is able to modulate signaling and growth of tumor cells that depend on HER1 and/or HER2. 

It is being developed by Ambit Biosciences/Bristol Myers Squibb Pharmaceuticals, and is presently in Phase I trials for patients with advanced solid tumors.

Common Name: BMS-599626
Synonyms:  AC480; BMS-599626; AC 480; AC-480; BMS 599626; BMS599626
IUPAC Name: (S)-morpholin-3-ylmethyl (4-((1-(3-fluorobenzyl)-1H-indazol-5-yl)amino)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl)carbamate
CAS Number: 714971-09-2; 873837-23-1 (hydrochloride)
Mechanism of Action: Kinase Inhibitior; EGFR Inhibitor; ERBB2 Inhibitor; ERBB4 Inhibitor
Indication: Various Cancers
Development Stage: Phase I

Company: Ambit Biosciences/Bristol Myers Squibb Pharmaceuticals

BMS-599626 inhibited HER1 and HER2 with IC50 of 20 and 30 nmol/L, respectively, and was highly selective when tested against a broad panel of diverse protein kinases. Biochemical studies suggested that BMS-599626 inhibited HER1 and HER2 through distinct mechanisms. BMS-599626 abrogated HER1 and HER2 signaling and inhibited the proliferation of tumor cell lines that are dependent on these receptors, with IC50 in the range of 0.24 to 1 micromol/L. BMS-599626 was highly selective for tumor cells that depend on HER1/HER2 and had no effect on the proliferation of cell lines that do not express these receptors. In tumor cells that are capable of forming HER1/HER2 heterodimers, BMS-599626 inhibited heterodimerization and downstream signaling. BMS-599626 had antitumor activity in models that overexpress HER1 (GEO), as well as in models that have HER2 gene amplification (KPL4) or overexpression (Sal2), and there was good correlation between the inhibition of receptor signaling and antitumor activity [1].

Phase I Study 

Researchers studied the safety, tolerability, and recommended dose of BMS-599626, an orally bioavailable inhibitor of the human epidermal growth factor receptor (HER) family of receptor tyrosine kinases [2].


Patients with advanced solid tumors that expressed epidermal growth factor receptor (EGFR) and/or HER-2 were recruited and enrolled in a Phase I, open-label, dose escalation trial of oral BMS-599626 starting at 100 mg/day given once daily for at least 28 days.


Forty-five patients received BMS-599626 (100–660 mg/day). Dose-limiting toxic effects were reported at 660 mg/day (grade 3 elevation of hepatic transaminases [two patients] and QTc interval prolongation [one patient]), therefore the recommended maximum tolerated dose was 600 mg/day. The most frequent drug-related toxic effects were diarrhea (30% of patients), anorexia (13%), asthenia (30%), and cutaneous toxic effects, including skin rash (30%). Pharmacokinetic analysis demonstrated Cmax and exposure to BMS-599626 in patients increased with dose. Eleven patients had stable disease and received BMS-599626 for =4 months. Serial skin and tumor biopsies taken before and after treatment revealed expected changes in pharmacodynamic biomarkers, indicating that the EGFR and HER-2 pathways were affected. Positron emission tomography imaging showed a metabolic response in 2 of 10 patients evaluated.

1. Wong, T. W.; et. al. Preclinical antitumor activity of BMS-599626, a pan-HER kinase inhibitor that inhibits HER1/HER2 homodimer and heterodimer signaling. Clin Cancer Res 2006, 12(20 Pt 1), 6186-6193.
2. Soria, J. C.; et. al. Phase I safety, pharmacokinetic and pharmacodynamic trial of BMS-599626 (AC480), an oral pan-HER receptor tyrosine kinase inhibitor, in patients with advanced solid tumors. Ann Oncol 2012, 23(2), 463-471.
3. Gavai, A. V.; et. al. Discovery and preclinical evaluation of [4-[[1-(3-fluorophenyl)methyl]-1H-indazol-5-ylamino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic acid, (3S)-3-morpholinylmethyl ester (BMS-599626), a selective and orally efficacious inhibitor of human epidermal growth factor receptor 1 and 2 kinases. J Med Chem 2009, 52(21), 6527-6530.