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Understanding the Role of Activation Loop Mutants in Drug Efficacy for FLT3-ITD

Kazi, Julhash U. LU orcid ; Al Ashiri, Lina LU orcid ; Purohit, Rituraj and Rönnstrand, Lars LU orcid (2023) In Cancers 15(22).
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... (More)

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.

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author
; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
drug sensitivity scores, four-parameter logistic curve, molecular docking, molecular modeling
in
Cancers
volume
15
issue
22
article number
5426
publisher
MDPI AG
external identifiers
  • pmid:38001685
  • scopus:85178144782
ISSN
2072-6694
DOI
10.3390/cancers15225426
language
English
LU publication?
yes
additional info
Funding Information: This research was supported by the Crafoord Foundation (J.U.K. # 20230775), the Swedish Cancer Society (J.U.K. #19 0004 FE and L.R. #21 1444 Pj), the Swedish Research Council (L.R. #2021-03055), the Swedish Childhood Cancer Foundation (J.U.K. # PR2022-0106), and SUS Stiftelser och Donationer (L.R. #95512), Governmental Funding of Clinical Research within the National Health Service (ALF) (L.R. # 40609). Publisher Copyright: © 2023 by the authors.
id
e133dd40-22cb-4218-b829-d923ce62f3d0
date added to LUP
2024-01-03 14:16:51
date last changed
2024-11-15 09:50:27
@article{e133dd40-22cb-4218-b829-d923ce62f3d0,
  abstract     = {{<p>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.</p>}},
  author       = {{Kazi, Julhash U. and Al Ashiri, Lina and Purohit, Rituraj and Rönnstrand, Lars}},
  issn         = {{2072-6694}},
  keywords     = {{drug sensitivity scores; four-parameter logistic curve; molecular docking; molecular modeling}},
  language     = {{eng}},
  number       = {{22}},
  publisher    = {{MDPI AG}},
  series       = {{Cancers}},
  title        = {{Understanding the Role of Activation Loop Mutants in Drug Efficacy for FLT3-ITD}},
  url          = {{http://dx.doi.org/10.3390/cancers15225426}},
  doi          = {{10.3390/cancers15225426}},
  volume       = {{15}},
  year         = {{2023}},
}