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AC480 (BMS-599626)

BMS-599626 is an orally bioavailable inhibitor of the HER1, HER2 and HER4 tyrosine kinases (IC₅₀=22, 32 and 190 nM, respectively) with potential antineoplastic activity. BMS-599626 inhibits human epidermal growth factor receptors (HER) HER1, HER2 and HER4, thereby inhibiting the proliferation of tumor cells that overexpress these receptors. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:   Ambit Biosciences, Inc.

AC480 (formerly BMS-599626) is a small molecule kinase inhibitor that selectively inhibits the HER family of receptors, HER1, HER2, and HER4. Ambit licensed worldwide rights to AC480 from Bristol-Myers Squibb (BMS) in October 2007, and is developing both an oral and an intravenous (IV) formulation of AC480.  An oral formulation of AC480 has been evaluated in multiple Phase 1/2 clinical trials and a recently completed Phase 2 clinical trial. At doses up to 600 mg/day, investigator assessments of efficacy in solid tumors across completed Phase 1 clinical trials indicated 25 (42%) patients had stable disease from three to 14 months and 17 patients (30%) had stable disease greater than five months. Most treatment-related adverse events were mild to moderate in severity, and included nausea, vomiting, diarrhea, fatigue, cough, elevation of the liver enzymes, and rash.

Oral AC480 was also evaluated in a Phase 2, open-label, dose-ranging and efficacy trial in advanced relapsed/refractory solid tumors. Results indicate that oral AC480 is generally well tolerated in patients taking a total of up to 600 mg/day administered on a twice-daily (BID) schedule with food. Of the 26 patients treated, 62% had stable disease. An intravenous (IV) formulation of AC480 was being developed (source: http://www.ambitbio.com).

Phase I study of AC-480:  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 C(max) 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. CONCLUSION:  BMS-599626 was generally well tolerated, with disease stabilization across a range of tumor types and doses. (source: Ann Oncol. 2012 Feb;23(2):463-71.).

1: Soria JC, Cortes J, Massard C, Armand JP, De Andreis D, Ropert S, Lopez E, Catteau A, James J, Marier JF, Beliveau M, Martell RE, Baselga J. 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 Feb;23(2):463-71. Epub 2011 May 16. PubMed PMID: 21576284.

2: Torres MA, Raju U, Molkentine D, Riesterer O, Milas L, Ang KK. AC480, formerly BMS-599626, a pan Her inhibitor, enhances radiosensitivity and radioresponse of head and neck squamous cell carcinoma cells in vitro and in vivo. Invest New Drugs. 2011 Aug;29(4):554-61. Epub 2010 Feb 2. PubMed PMID: 20119866.

3: Gavai AV, Fink BE, Fairfax DJ, Martin GS, Rossiter LM, Holst CL, Kim SH, Leavitt KJ, Mastalerz H, Han WC, Norris D, Goyal B, Swaminathan S, Patel B, Mathur A, Vyas DM, Tokarski JS, Yu C, Oppenheimer S, Zhang H, Marathe P, Fargnoli J, Lee FY, Wong TW, Vite GD. 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 Nov 12;52(21):6527-30. PubMed PMID: 19821562.

4: Wong TW, Lee FY, Yu C, Luo FR, Oppenheimer S, Zhang H, Smykla RA, Mastalerz H, Fink BE, Hunt JT, Gavai AV, Vite GD. Preclinical antitumor activity of BMS-599626, a pan-HER kinase inhibitor that inhibits HER1/HER2 homodimer and heterodimer signaling. Clin Cancer Res. 2006 Oct 15;12(20 Pt 1):6186-93. PubMed PMID: 17062696.