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Fungal secondary metabolites as a potential inhibitor of T315I- BCR::ABL1 mutant in chronic myeloid leukemia by molecular docking, molecular dynamics simulation and binding free energy exploration approaches.
J Genet Eng Biotechnol
December 2024
Hematologic Disease Center, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Medical University, Urumqi 830011, China. Electronic address:
Background: Chronic Myeloid Leukemia (CML) is particularly challenging to treat due to the T315I BCR::ABL1 mutation. Although fungal metabolites are known for their pharmaceutical potential, none are approved for CML. Our study screened approximately 2000 fungal secondary metabolites to discover inhibitors targeting the T315I- BCR::ABL1 mutant protein.
View Article and Find Full Text PDFExploring Inhibition Mechanisms in Wildtype and T315I BCR-ABL1: An In Silico Approach Integrating Virtual Screening, MD Simulations, and MM-GBSA Analysis.
J Comput Chem
January 2025
Department of Bioinformatics, Institute of Health Sciences, Karadeniz Technical University, Trabzon, Turkey.
The BCR-ABL tyrosine kinase which is responsible for the pathogenesis of chronic myeloid leukemia (CML), has emerged as a promising therapeutic target. To address this issue, we employed a comprehensive computational approach integrating virtual screening, molecular dynamics (MD) simulations, and MM-GBSA (Molecular Mechanics/Generalized Born Surface Area) analysis to identify potential inhibitors and elucidate their binding mechanisms. Initially, virtual screening was conducted on 994 compounds from the ZINC database and, these compounds were docked against wildtype and T315I mutant ABL1 for the Type I and Type II ABL1 kinase inhibition mechanisms.
View Article and Find Full Text PDFComputationally Driven Discovery of a BCR-ABL1 Kinase Inhibitor with Activity in Multidrug-Resistant Chronic Myeloid Leukemia.
J Med Chem
October 2024
Department of Pharmaceutical and Biomedical Sciences, University of Georgia, 250 West Green Street, Athens, Georgia 30602, United States.
The permeability glycoprotein, encoded by the gene, is widely implicated in multidrug resistance (MDR), as it has been shown to reduce the intracellular concentration of most small molecule therapeutics, including the majority of the breakpoint cluster region Abelson proto-oncogene 1 (BCR-ABL1) kinase inhibitors used in the treatment of Philadelphia chromosome positive (Ph+) leukemias. With this in mind, we describe an integrated theoretical and experimental approach to shed light on substituent effects in the pendant anilino moiety of 4-anilinoquinazolines and 4-anilinoquinoline-3-carbonitrile-based kinase inhibitors and their influence on P-gp-mediated efflux. This analysis culminated in the identification of a hydroxylamine-bearing, dual cSRC/BCR-ABL1 kinase inhibitor that exhibits a marked reduction in P-gp-mediated efflux ratio and potent activity in a Ph+ patient-derived cell line (K562) and an MDR-Ph+ patient-derived cell line (K562/Dox) overexpressing P-gp.
View Article and Find Full Text PDFDecitabine, venetoclax, and ponatinib for advanced phase chronic myeloid leukaemia and Philadelphia chromosome-positive acute myeloid leukaemia: a single-arm, single-centre phase 2 trial.
Lancet Haematol
November 2024
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Article Synopsis
Overcoming clinical BCR-ABL1 compound mutant resistance with combined ponatinib and asciminib therapy.
Cancer Cell
September 2024
Division of Hematology & Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA. Electronic address:
BCR-ABL1 compound mutations can lead to resistance to ABL1 inhibitors in chronic myeloid leukemia (CML), which could be targeted by combining the ATP-site inhibitor ponatinib and the allosteric inhibitor asciminib. Here, we report the clinical validation of this approach in a CML patient, providing a basis for combination therapy to overcome such resistance.
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