Allosteric inhibitors of Bcr-abl–dependent cell proliferation

Abstract

Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized at the molecular level by the expression of Bcr-abl, a 210-kDa fusion protein with deregulated tyrosine kinase activity. Encouraged by the clinical validation of Bcr-abl as the target for the treatment of CML by imatinib, we sought to identify pharmacological agents that could target this kinase by a distinct mechanism. We report the discovery of a new class of Bcr-abl inhibitors using an unbiased differential cytotoxicity screen of a combinatorial kinase-directed heterocycle library. Compounds in this class (exemplified by GNF-2) show exclusive antiproliferative activity toward Bcr-abl-transformed cells, with potencies similar to imatinib, while showing no inhibition of the kinase activity of full-length or catalytic domain of c-abl. We propose that this new class of compounds inhibits Bcr-abl kinase activity through an allosteric non-ATP competitive mechanism.

Curcumin derivative C817 inhibits proliferation of imatinib-resistant chronic myeloid leukemia cells with wild-type or mutant Bcr-Abl in vitro

“…Thus, it is urgent to To achieve this goal, some small molecule compounds have been designed to target Bcr-Abl motifs remote from the kinase domain. The activity of these drugs remains unaffected by the presence of mutations in the kinase domain of the enzyme, including ON012380, GNF-2, and GNF-5 [13,14,[28][29][30][31] . GNF-5, an analog of GNF-2 having improved pharmacokinetic properties, when combined with the ATP-competitive inhibitors imatinib or, can suppressed the emergence of resistance mutations in vitro, displayed inhibitory activity against T315I Bcr-Abl and displayed in vivo efficacy against the recalcitrant T315I Bcr-Abl mutant in a murine bone-marrow transplantation model.…”

“…Two recently approved drugs nilotinib and dasatinib are able to override the majority of the imatinib resistance mutations with the exception of T315I mutation, which is situated in the middle of the ATP-binding cleft [6][7][8][9][10][11][12] . GNF-2, a selective allosteric Bcr-Abl inhibitor, is new pharmacological modality to overcome resistance to ATP-site inhibitors of BcrAbl [13,14] . GNF-2 binds to the myristate binding site of Abl, leading to changes in the structural dynamics of the ATPbinding site.…”

Allosterische Kinaseinhibitoren

“…Unerwartet war allerdings, dass die T315I-Gatekeeper-Mutation, welche gegen alle zugelassenen BCR-ABL1-Inhibitoren außer Ponatinib resistent ist, ebenso wie eine kleine Zahl anderer Mutationen nicht durch GNF-2 inhibierbar war [1]. Dies ist insbesondere verwunderlich, wenn man bedenkt, wie weit diese Mutation von der Myristat-Bindungstasche entfernt ist und daher nicht sterisch mit der GNF-2-Bindung interferieren kann.…”

Proteus in the World of Proteins: Conformational Changes in Protein Kinases

“…Myristate binding itself does not, however, affect the conformation of the active site of Abl [65]. GNF-2, an Abl inhibitor that occupies the myristate binding site of Abl, is potent in cellular systems (where full length Abl is present) and biochemical assays where the isolated kinase domain of Abl is used [66]. In addition, a c-Abl isoform lacking the N-myristoyl residue was shown to be approximately 100-fold more sensitive to inhibition by GNF-2.…”