Discovery of [1,2,4]triazolo[1,5-a]pyrimidine-Imatinib Hybrids With Selective Cytotoxic Activity: A Mechanistically Divergent Series From Direct BCR-ABL1 Inhibition.
2/5 보강
OpenAlex 토픽 ·
Chronic Myeloid Leukemia Treatments
Synthesis and biological activity
Click Chemistry and Applications
Chronic myeloid leukemia treatment faces the challenge of resistance to BCR-ABL1 tyrosine kinase inhibitors.
APA
Stefany Castro Bazan Moura, Andressa Paula de Oliveira, et al. (2026). Discovery of [1,2,4]triazolo[1,5-a]pyrimidine-Imatinib Hybrids With Selective Cytotoxic Activity: A Mechanistically Divergent Series From Direct BCR-ABL1 Inhibition.. ChemMedChem, 21(8), e202501100. https://doi.org/10.1002/cmdc.202501100
MLA
Stefany Castro Bazan Moura, et al.. "Discovery of [1,2,4]triazolo[1,5-a]pyrimidine-Imatinib Hybrids With Selective Cytotoxic Activity: A Mechanistically Divergent Series From Direct BCR-ABL1 Inhibition.." ChemMedChem, vol. 21, no. 8, 2026, pp. e202501100.
PMID
42001524 ↗
Abstract 한글 요약
Chronic myeloid leukemia treatment faces the challenge of resistance to BCR-ABL1 tyrosine kinase inhibitors. To address this, we rationally designed six new imatinib-derived compounds 2(a-f) by replacing the quinoline moiety with a [1,2,4]triazolo[1,5-a]pyrimidine scaffold via classical bioisosterism. The compounds were efficiently synthesized and characterized. Biological evaluation revealed that compound 2a exhibited cytotoxic activity in BCR-ABL1-positive K562 cells (47% viability inhibition at 10 µM, IC = 9.7 µM). However, enzymatic assays demonstrated that 2a does not directly inhibit the wild-type ABL1 kinase, unlike IMT. This finding, coupled with its cytotoxicity in nontumorigenic WSS-1 cells, indicates an alternative, off-target mechanism. A clear structure-activity relationship identified the detrimental effect of a -CF substitution. Overall, this work applies bioisosteric replacement to generate a new chemotype and uncovers a mechanistically divergent lead. The distinct, ABL1-independent mechanism of compound 2a establishes a solid foundation for future optimization and highlights its potential as a starting point for developing novel antimyeloproliferative agents with a different therapeutic profile.
🏷️ 키워드 / MeSH 📖 같은 키워드 OA만
- Humans
- Fusion Proteins
- bcr-abl
- Structure-Activity Relationship
- Antineoplastic Agents
- Protein Kinase Inhibitors
- Pyrimidines
- Drug Screening Assays
- Antitumor
- Triazoles
- Cell Proliferation
- Molecular Structure
- Imatinib Mesylate
- Dose-Response Relationship
- Drug
- Drug Discovery
- K562 Cells
- Cell Survival
- BCR‐ABL1
- chronic myeloid leukemia
- drug discovery
- enzymes
- medicinal chemistry
🏷️ 같은 키워드 · 무료전문 — 이 논문 MeSH/keyword 기반
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