Kazi, J.U.; Al Ashiri, L.; Purohit, R.; Rönnstrand, L. Understanding the Role of Activation Loop Mutants in Drug Efficacy for FLT3-ITD. Cancers2023, 15, 5426.
Kazi, J.U.; Al Ashiri, L.; Purohit, R.; Rönnstrand, L. Understanding the Role of Activation Loop Mutants in Drug Efficacy for FLT3-ITD. Cancers 2023, 15, 5426.
Kazi, J.U.; Al Ashiri, L.; Purohit, R.; Rönnstrand, L. Understanding the Role of Activation Loop Mutants in Drug Efficacy for FLT3-ITD. Cancers2023, 15, 5426.
Kazi, J.U.; Al Ashiri, L.; Purohit, R.; Rönnstrand, L. Understanding the Role of Activation Loop Mutants in Drug Efficacy for FLT3-ITD. Cancers 2023, 15, 5426.
Abstract
The type III receptor tyrosine kinase FLT3 is a pivotal kinase for hematopoietic progenitor cell regulation, with significant implications in acute myeloid leukemia (AML) through mutations like internal tandem duplication (ITD). This study delves into the structural intricacies of FLT3, the roles of activation loop mutants, and their interaction with tyrosine kinase inhibitors. Coupled with this, the research leverages molecular contrastive learning and protein language modeling to examine interactions between small molecule inhibitors and FLT3 activation loop mutants. Utilizing the ConPLex platform, over 5.7 million unique FLT3 activation loop mutants-small molecule pairs were analyzed. The binding free energies of three inhibitors were assessed, and cellular apoptotic responses were evaluated under drug treatments. Notably, the introduction of the Xepto50 scoring system provides a nuanced metric for drug efficacy. The findings underscore the modulation of molecular interactions and cellular responses by Y842 mutations in FLT3-KD, highlighting the need for tailored therapeutic approaches in FLT3-ITD-related malignancies.
Keywords
drug sensitivity scores; molecular modeling; molecular docking; four-parameter logistic curve
Subject
Medicine and Pharmacology, Hematology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
