, Volume 58, Issue 1 Supplement, pp 55-61
Date: 09 Nov 2006

Development of NS-187, a potent and selective dual Bcr-Abl/Lyn tyrosine kinase inhibitor

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Abstract

Imatinib mesylate (Gleevec™) has improved the treatment of Bcr-Abl-positive leukemia. However, resistance is often reported in patients with advanced-stage disease. Chemical modifications of imatinib made with the guidance of molecular modeling have yielded several promising compounds that could override imatinib resistance. Among them, we selected a compound denoted NS-187. The most striking structural characteristic of NS-187 is its trifluoromethyl group at position 3 of the benzamide ring, which strengthens the hydrophobic interactions and fixes the conformation of the compound. NS-187 was 25–55 times more potent than imatinib against wild-type Bcr-Abl in vitro. At physiological concentrations, NS-187 also inhibited the phosphorylation and growth of all Bcr-Abl mutants tested except T315I. In addition to Bcr-Abl, NS-187 also inhibited Lyn, which might be involved in imatinib resistance, without affecting the phosphorylation of Src, Blk, or Yes. This indicates that NS-187 acts as a dual Bcr-Abl/Lyn inhibitor. Our proposed docking models of the NS-187/Abl complex support the notion that NS-187 is more specific for Lyn than for Src. In Balb/c-nu/nu mice, which were injected subcutaneously with Bcr-Abl-positive KU812 cells, NS-187 showed at least tenfold more potency than imatinib. We also tested the ability of NS-187 to suppress tumor growth in another murine tumor model, namely, Balb/c-nu/nu mice intravenously transplanted with BaF3 cells harboring wild-type or several mutations of Bcr-Abl (M244V, G250E, Q252H, Y253F, E255K, T315I, M351T, and H396P). NS-187 prolonged the survival of mice injected with leukemic cells expressing wild-type or all mutated Bcr-Abl except T315I, and its efficacy correlated well with its in vitro effects. NS-187 also inhibited leukemic cells harboring wild-type Bcr-Abl growth in the central nervous system, which sometimes becomes a sanctuary for leukemic cells under imatinib treatment. These results suggest that NS-187 may be a potentially valuable novel agent to combat imatinib-resistant Bcr-Abl-positive leukemia. A phase I study of NS-187 will start in 2006.

This work was presented at the 21st Bristol-Myers Squibb Nagoya International Cancer Treatment Symposium, “Lung Cancer: Novel Therapy against Malfunctioning Molecules”, 24–25 February 2006, Nagoya, Japan.