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Journal Article
Bcr-Abl Allosteric Inhibitors: Where We Are and Where We Are Going to
2020
Overview
The fusion oncoprotein Bcr-Abl is an aberrant tyrosine kinase responsible for chronic myeloid leukemia and acute lymphoblastic leukemia. The auto-inhibition regulatory module observed in the progenitor kinase c-Abl is lost in the aberrant Bcr-Abl, because of the lack of the N-myristoylated cap able to bind the myristoyl binding pocket also conserved in the Bcr-Abl kinase domain. A way to overcome the occurrence of resistance phenomena frequently observed for Bcr-Abl orthosteric drugs is the rational design of allosteric ligands approaching the so-called myristoyl binding pocket. The discovery of these allosteric inhibitors although very difficult and extremely challenging, represents a valuable option to minimize drug resistance, mostly due to the occurrence of mutations more frequently affecting orthosteric pockets, and to enhance target selectivity with lower off-target effects. In this perspective, we will elucidate at a molecular level the structural bases behind the Bcr-Abl allosteric control and will show how artificial intelligence can be effective to drive the automated de novo design towards off-patent regions of the chemical space.
Publisher
MDPI,MDPI AG
Subject
/ Allosteric Regulation - drug effects
/ Animals
/ Antineoplastic Agents - pharmacology
/ Bcr-Abl
/ Chemistry, Pharmaceutical - methods
/ Chemistry, Pharmaceutical - trends
/ Fusion Proteins, bcr-abl - antagonists & inhibitors
/ Humans
/ Mice
/ Molecular Docking Simulation
