FLT3-ITD-Specific PROTAC: Enhanced Safety and Increased Synergy with Venetoclax in Acute Myeloid Leukemia DOI Creative Commons
Yuxin Tan, Lilan Xin, Qian Wang

et al.

Research Square (Research Square), Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 6, 2023

Abstract Background Patients with acute myeloid leukemia (AML) carrying Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations often face a poor prognosis, high risk of relapse, and short overall survival. While some FLT3 small molecule inhibitors have been used clinically, challenges such as efficacy, specificity, resistance persist. Proteolytic targeting chimera (PROTAC), its lower ligand affinity requirement for target proteins, offers higher capability, the minimal amount PROTAC can rapidly degrade proteins. This technology may address issues specificity or seen inhibitors. Methods Gilteritinib was protein FLT3-ITD, different E3 ligase ligands were connected to synthesize several series FLT3-ITD. Results Through in vitro vivo screening structural optimization, Z29 linked VHL ligand, optimal lead compound, obtained. Kinase showed that synthesized exhibited better ability than existing In , significantly inhibited proliferation FLT3-ITD + MOLM13 MV-4-11 cells induced degradation through proteasome pathway at nanomolar level. tumor growth rate dose 30 mg/kg subcutaneous xenograft mice while maintaining stable body weight mice. Compared Gilteritinib, when combination Venetoclax, demonstrated synergy score cells. We also verified 's impact on platelets patient-derived xenografts (PDX) model, which be due expression platelets. The Venetoclax anti-tumor effects platelet toxicity hepatic toxicity. Conclusion enhance drug specificity. rapid mitigate inhibitors, ensuring safety efficacy monotherapy therapy. These findings establish solid foundation FLT3-ITD-PROTAC an effective strategy treatment patients mutation.

Language: Английский

FLT3-selective PROTAC: Enhanced safety and increased synergy with Venetoclax in FLT3-ITD mutated acute myeloid leukemia DOI
Yuxin Tan, Lilan Xin, Qian Wang

et al.

Cancer Letters, Journal Year: 2024, Volume and Issue: 592, P. 216933 - 216933

Published: May 4, 2024

Language: Английский

Citations

7
Understanding the Role of Activation Loop Mutants in Drug Efficacy for FLT3-ITD DOI Open Access
Julhash U. Kazi,

Lina Al Ashiri,

Rituraj Purohit

et al.

Cancers, Journal Year: 2023, Volume and Issue: 15(22), P. 5426 - 5426

Published: Nov. 15, 2023

The type III receptor tyrosine kinase FLT3 is a pivotal 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, roles activation loop mutants, and their interaction inhibitors. Coupled this, research leverages molecular contrastive learning protein language modeling to examine interactions between small molecule inhibitors mutants. Utilizing ConPLex platform, over 5.7 million unique mutants-small pairs were analyzed. binding free energies three assessed, cellular apoptotic responses evaluated under drug treatments. Notably, introduction Xepto50 scoring system provides nuanced metric efficacy. findings underscore modulation by Y842 FLT3-KD, highlighting need tailored therapeutic approaches FLT3-ITD-related malignancies.

Language: Английский

Citations

4
The safety and efficacy of the re-administration of gilteritinib in a patient with FLT3-mutated R/R AML with CNS relapse: a case report DOI Creative Commons

Yue-Ru Ji,

Zhuo Wan, Jian Yang

et al.

Frontiers in Oncology, Journal Year: 2024, Volume and Issue: 14

Published: July 2, 2024

FLT3-ITD is a type of poor prognostic factors in acute myeloid leukemia (AML) disease. Gilteritinib, the second-generation FLT3 tyrosine kinase inhibitor, improved overall survival patients with relapsed/refractory FLT3-mutated AML ADMIRAL phase III trial. However, few data are available on efficacy and safety gilteritinib-based therapy for central nervous system (CNS) involvement. We performed gilteritinib to treat patient CNS relapsed after allogeneic hematopoietic stem cell transplantation. The positive antileukemic effect may bring new hope treatment relapse.

Language: Английский

Citations

1
Understanding the characteristic behavior of the wild-type and mutant protein structure of FLT3 protein by computational methods DOI Open Access
Saleena Younus,

Özge Tatli,

Ahmad Nasimian

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 21, 2024

Abstract FLT3 emerges as a commonly mutated protein with significant prognostic implications in acute myeloid leukemia (AML). Point mutations or deletions the tyrosine kinase domain (TKD) at activation loop and internal tandem duplications (ITD) juxtamembrane (JM) region (and less TKD) are primary that occur protein. Besides, AML treatment inhibitor drugs may result acquisition of TKD FLT3-ITD structure. All these will induce activity leading to downstream signaling pathways. Therefore, finding better therapeutics against each mutant proteins is crucial AML. This study aims comprehend characteristic behavior mutants (C F Y842), ITD mutants, combination Y842) through computational approaches, including Molecular Dynamic (MD) simulation, cluster analysis, machine learning techniques. The MD simulation studies revealed alterations optimized state, flexibility, compactness nature between FLT3-WT identified changes point ITD, combined structures. Cluster analysis also confirmed significantly impact overall flexibility structures, especially point-mutated structures FLT3-Y842C FLT3-ITD-Y842F. These findings emphasize diverse conformations protein, contributing deregulation function, promising therapeutic targets

Language: Английский

Citations

0
Identification of a novel mutation of the FLT3 gene located on the juxtamembrane domain from acute myeloid leukemia patients DOI

Elly Yanah Arwanih,

Ikhwan Rinaldi, Septelia Inawati Wanandi

et al.

Molecular Biology Reports, Journal Year: 2024, Volume and Issue: 51(1)

Published: July 29, 2024

Language: Английский

Citations

0
FLT3-ITD-Specific PROTAC: Enhanced Safety and Increased Synergy with Venetoclax in Acute Myeloid Leukemia DOI Creative Commons
Yuxin Tan, Lilan Xin, Qian Wang

et al.

Research Square (Research Square), Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 6, 2023

Abstract Background Patients with acute myeloid leukemia (AML) carrying Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations often face a poor prognosis, high risk of relapse, and short overall survival. While some FLT3 small molecule inhibitors have been used clinically, challenges such as efficacy, specificity, resistance persist. Proteolytic targeting chimera (PROTAC), its lower ligand affinity requirement for target proteins, offers higher capability, the minimal amount PROTAC can rapidly degrade proteins. This technology may address issues specificity or seen inhibitors. Methods Gilteritinib was protein FLT3-ITD, different E3 ligase ligands were connected to synthesize several series FLT3-ITD. Results Through in vitro vivo screening structural optimization, Z29 linked VHL ligand, optimal lead compound, obtained. Kinase showed that synthesized exhibited better ability than existing In , significantly inhibited proliferation FLT3-ITD + MOLM13 MV-4-11 cells induced degradation through proteasome pathway at nanomolar level. tumor growth rate dose 30 mg/kg subcutaneous xenograft mice while maintaining stable body weight mice. Compared Gilteritinib, when combination Venetoclax, demonstrated synergy score cells. We also verified 's impact on platelets patient-derived xenografts (PDX) model, which be due expression platelets. The Venetoclax anti-tumor effects platelet toxicity hepatic toxicity. Conclusion enhance drug specificity. rapid mitigate inhibitors, ensuring safety efficacy monotherapy therapy. These findings establish solid foundation FLT3-ITD-PROTAC an effective strategy treatment patients mutation.

Language: Английский

Citations

0