Amuvatinib - CAS 850879-09-3
Catalog number: 850879-09-3
Category: Inhibitor
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Amuvatinib, also known as MP-470, is an orally bioavailable synthetic carbothioamide with potential antineoplastic activity. MP470 inhibits activities of other receptor tyrosine kinases. This agent also suppresses the induction of DNA repair protein Rad51, thereby potentiating the activities of DNA damage-inducing agents.
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HPK 56; HPK-56; HPK56; MP-470; MP470; MP 470.
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SuperGen, Inc
1.Amuvatinib has cytotoxic effects against NRAS-mutant melanoma but not BRAF-mutant melanoma.
Fedorenko IV1, Fang B, Koomen JM, Gibney GT, Smalley KS. Melanoma Res. 2014 Oct;24(5):448-53. doi: 10.1097/CMR.0000000000000103.
Effective targeted therapy strategies are still lacking for the 15-20% of melanoma patients whose melanomas are driven by oncogenic NRAS. Here, we report on the NRAS-specific behavior of amuvatinib, a kinase inhibitor with activity against c-KIT, Axl, PDGFRα, and Rad51. An analysis of BRAF-mutant and NRAS-mutant melanoma cell lines showed the NRAS-mutant cohort to be enriched for targets of amuvatinib, including Axl, c-KIT, and the Axl ligand Gas6. Increasing concentrations of amuvatinib selectively inhibited the growth of NRAS-mutant, but not BRAF-mutant melanoma cell lines, an effect associated with induction of S-phase and G2/M-phase cell cycle arrest and induction of apoptosis. Mechanistically, amuvatinib was noted to either inhibit Axl, AKT, and MAPK signaling or Axl and AKT signaling and to induce a DNA damage response. In three-dimensional cell culture experiments, amuvatinib was cytotoxic against NRAS-mutant melanoma cell lines. Thus, we show for the first time that amuvatinib has proapoptotic activity against melanoma cell lines, with selectivity observed for those harboring oncogenic NRAS.
2.Targeting MET kinase with the small-molecule inhibitor amuvatinib induces cytotoxicity in primary myeloma cells and cell lines.
Phillip CJ, Zaman S, Shentu S, Balakrishnan K, Zhang J, Baladandayuthapani V, Taverna P, Redkar S, Wang M, Stellrecht CM, Gandhi V1. J Hematol Oncol. 2013 Dec 10;6:92. doi: 10.1186/1756-8722-6-92.
BACKGROUND: MET is a receptor tyrosine kinase that is activated by the ligand HGF and this pathway promotes cell survival, migration, and motility. In accordance with its oncogenic role, MET is constitutively active, mutated, or over-expressed in many cancers. Corollary to its impact, inhibition of MET kinase activity causes reduction of the downstream signaling and demise of cells. In myeloma, a B-cell plasma malignancy, MET is neither mutated nor over-expressed, however, HGF is increased in plasma or serum obtained from myeloma patients and this was associated with poor prognosis. The small-molecule, amuvatinib, inhibits MET receptor tyrosine kinase. Based on this background, we hypothesized that targeting the HGF/MET signaling pathway is a rational approach to myeloma therapy and that myeloma cells would be sensitive to amuvatinib.
3.A phase I, first-in-human dose-escalation study of amuvatinib, a multi-targeted tyrosine kinase inhibitor, in patients with advanced solid tumors.
Tibes R1, Fine G, Choy G, Redkar S, Taverna P, Oganesian A, Sahai A, Azab M, Tolcher AW. Cancer Chemother Pharmacol. 2013 Feb;71(2):463-71. doi: 10.1007/s00280-012-2019-3. Epub 2012 Nov 23.
PURPOSE: Amuvatinib is a novel orally administered tyrosine kinase inhibitor with in vitro pharmacological activity against mutant KIT, platelet-derived growth factor receptor alpha (PDGFRα), and Rad51. Amuvatinib was investigated in a first-in-human, single-agent, phase I, accelerated titration, dose-escalation trial ( identifier: NCT00894894) in patients with solid tumors refractory to prior therapies or for which no standard therapy existed.METHODS: Twenty-two patients received amuvatinib dry powder capsules (DPC) from 100 to 1,500 mg daily in 28-day cycles. Safety, preliminary efficacy, pharmacologic activity, and pharmacokinetics were investigated.
4.Safety, tolerability, and pharmacokinetics of amuvatinib from three phase 1 clinical studies in healthy volunteers.
Choy G1, Joshi-Hangal R, Oganesian A, Fine G, Rasmussen S, Collier J, Kissling J, Sahai A, Azab M, Redkar S. Cancer Chemother Pharmacol. 2012 Jul;70(1):183-90. doi: 10.1007/s00280-012-1821-2. Epub 2012 Feb 15.
PURPOSE: Amuvatinib is a multi-targeted tyrosine kinase inhibitor with activity that also disrupts DNA damage repair through suppression of homologous recombination protein Rad51. Amuvatinib dry-powder capsules (DPC) showed evidence of activity in early Phase 1 cancer studies but low systemic exposure. The purposes of the studies were to investigate the cause of low exposure, develop, and test an alternative formulation with improved exposure, and establish the dose to be tested in future studies in cancer patients.
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CAS 850879-09-3 Amuvatinib

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