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2000
Volume 25, Issue 19
  • ISSN: 1871-5206
  • E-ISSN: 1875-5992

Abstract

Background

The occurrence of gain of function mutations in has been associated to survival, and drug resistance in Leukemia. screening of compounds having inhibitory potential towards mutated proteins, can be helpful in the development of specific inhibitors.

Objective

This study was designed to screen selected mutations in leukemia patients and virtual exploration of molecular interaction of potential inhibitors with their mutated products.

Methods

In total 276 patients were randomly recruited for this study. Demographic and clinical data were summarized. The genetic status of JAK1V623A, JAK2 S473 and STAT5BN642H were screened through allele specific PCR. analysis was performed on wild type and mutant protein sequences retrieved from Protein databank. The ligands and protein were prepared through standard protocols, and docking was performed through Auto Dock Vina 1.2.0.

Results

Acute lymphoblastic leukemia comprises 70% of the total patients. Male to female ratio was 3:1. All the patients were homozygous for JAK1V623A, JAK2 S473 major allele. However, 6 patients (5 male, 1 female) with ALL were STAT5BN642H+. The molecular docking of the ligands to wild type and STAT5BN642H+revealed that AC-4-130, Pimozide, Indirubin and Stafib-2 have higher but differential docking affinities for SH2-domain of both normal and mutated . However, AC-4-130 has a higher affinity for wild type and Stafib-2 has stable molecular interaction with STAT5BN642H+.

Conclusion

The aggressive form of pediatric leukemia, carrying STAT5BN642H mutation is identified in the studied population. It is predicted that AC-14-30 and stafib-2 have potential for inhibition of constitutively active STAT5B if optimized for use in combination therapy.

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Recurrent Missense Driver STAT5B N642H Mutation in Children Transiting into Adolescence, with Acute Lymphoid Leukemia and its In silico Inhibition
Anti-Cancer Agents in Medicinal Chemistry 25, 1536 (2025); https://doi.org/10.2174/0118715206350463241226032324
/content/journals/acamc/10.2174/0118715206350463241226032324
/content/journals/acamc/10.2174/0118715206350463241226032324
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  • Article Type:     Research Article
Keyword(s): AC-4-130; aggressive leukemia; personalized therapy; stafib-2; STAT5BN642H; targeted inhibition

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