A Synergistic Combination Against Chronic Myeloid Leukemia: An Intra-molecular Mechanism of Communication in BCR-ABL1 Resistance

Protein J. 2019 Apr;38(2):142-150. doi: 10.1007/s10930-019-09820-z.

Abstract

The constitutive BCR-ABL1 active protein fusion has been identified as the main cause of chronic myeloid leukemia. The emergence of T334I and D381N point mutations in BCR-ABL1 confer drug resistance. Recent experimental studies show a synergistic effect in suppressing this resistance when Nilotinib and Asciminib are co-administered to target both the catalytic and allosteric binding site of BCR-ABL1 oncoprotein, respectively. However, the structural mechanism by which this synergistic effect occurs has not been clearly elucidated. To obtain insight into the observed synergistic effect, molecular dynamics simulations have been employed to investigate the inhibitory mechanism as well as the structural dynamics that characterize this effect. Structural dynamic analyses indicate that the synergistic binding effect results in a more compact and stable protein conformation. In addition, binding free energy calculation suggests a dominant energy effect of nilotinib during co-administration. van der Waals energy interactions were observed to be the main energy component driving this synergistic effect. Furthermore, per-residue energy decomposition analysis identified Glu481, Ser453, Ala452, Tyr454, Phe401, Asp400, Met337, Phe336, Ile334, And Val275 as key residues that contribute largely to the synergistic effect. The findings highlighted in this study provide a molecular understanding of the dynamics and mechanisms that mediate the synergistic inhibition in BCR-ABL1 protein in chronic myeloid leukemia treatment.

Keywords: Allosteric inhibitor; Asciminib (ABL001); BCR–ABL1; CML; Molecular dynamics; Mutation; Nilotinib.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols*
  • Drug Resistance, Neoplasm* / drug effects
  • Drug Resistance, Neoplasm* / genetics
  • Drug Synergism
  • Fusion Proteins, bcr-abl / genetics
  • Fusion Proteins, bcr-abl / metabolism*
  • Humans
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
  • Molecular Dynamics Simulation
  • Mutation
  • Niacinamide / analogs & derivatives*
  • Niacinamide / pharmacology
  • Niacinamide / therapeutic use
  • Pyrazoles / pharmacology*
  • Pyrazoles / therapeutic use
  • Pyrimidines / pharmacology*
  • Pyrimidines / therapeutic use

Substances

  • 4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide
  • Pyrazoles
  • Pyrimidines
  • asciminib
  • Niacinamide
  • Fusion Proteins, bcr-abl