Dual Drug Targeting of Mutant Bcr‐Abl Induces Inactive Conformation: New Strategy for the Treatment of Chronic Myeloid Leukemia and Overcoming Monotherapy Resistance

Citations Over TimeTop 19% of 2018 papers

Abstract

Bcr-Abl is an oncogenic fusion protein which expression enhances tumorigenesis, and has been highly associated with chronic myeloid leukemia (CML). Acquired drug resistance in mutant Bcr-Abl has enhanced pathogenesis with the use of single therapy agents such as nilotinib. Moreover, allosteric targeting has been identified to consequentially inhibit Bcr-Abl activity, which led to the recent development of ABL-001 (asciminib) that selectively binds the myristoyl pocket. Experimental studies have revealed that the combination of nilotinib and ABL-001 induced a 'bent' conformation in the C-terminal helix of Bcr-Abl; a benchmark of inhibition, thereby exhibiting a greater potency in the treatment of CML, surmounting the setbacks of drug resistance, disease regression and relapse. Therefore, we report the first account of the dynamics and conformational analysis of oncogenic T334I Bcr-Abl by dual targeting. Our findings revealed that unlike in the Bcr-Abl-Nilotinib complex, dual targeting by both inhibitors induced the bent conformation in the C-terminal helix that varied with time. This was coupled with significant alteration in Bcr-Abl stability, flexibility, and compactness and an overall structural re-orientation inwards towards the hydrophobic core, which reduced the solvent-exposed residues indicative of protein folding. This study will facilitate allosteric targeting and the design of more potent allosteric inhibitors for resistive target proteins in cancer.

Related Papers

• → Sporulation in Bacillus subtilis. Characterization of Oligosporogenous Mutants and Comparison of Their Phenotypes with Those of Asporogenous Mutants(1972)137 cited
• → The Novel Symbiotic Phenotype of Enhanced-Nodulating Mutant of Lotus japonicus: astray Mutant is an Early Nodulating Mutant with Wider Nodulation Zone(2002)60 cited
• → A new set of adsorption mutants of bacteriophage T4D: Identification of a new gene(1974)29 cited
• → Studies on a Temperature-sensitive Irreparable Mutant of <i>Neurospora Crassa</i>(1960)11 cited
• Phenotypic and genetic analysis of two reverse rolled leaf mutants(2014)