| DOI: 10.29090/psa.2026.04.26.9817 | Pharm Sci Asia 2026; 53(4), 430-443 |
Selective targeting of p38 MAP kinase and beyond: Triazole-based heterocycles in anticancer drug discoveryCheela Keerthi 1, Ramesh Kola 2*, Kantalam Chamakuri 3
1 Department of Chemistry, Bharatiya Science and Technology Innovation University, Anantapur, Andhra Pradesh, India.
2 Department of Chemistry, Chaitanya Bharathi Institute of Technology, Gandipet, Hyderabad, Telangana, India.
3 Faculty of Pharmacy, Brilliant group of Institutions, Hyderabad, Telangana, India.
The p38 MAP kinase signaling pathway is pivotal in modulating cellular responses to stress stimuli, inflammatory cytokines, and growth factors. The dysregulation of this system strongly contributes to cancer growth, metastasis, inflammation, and therapy resistance, rendering p38 MAP kinase a compelling molecular target for anticancer drug development. In recent years, triazole-based scaffolds, particularly 1,2,3- and 1,2,4-triazoles, have gained significant attention due to their favorable physicochemical properties, metabolic stability, and ability to interact effectively with kinase active sites. This review encapsulates current progress in triazole-based p38 MAP kinase inhibitors, emphasizes insights into SAR, and examines new perspectives for enhancing these scaffolds to generate selective and clinically efficacious anticancer drugs. SAR analysis reveals that strategic substitution, heterocyclic hybridization, and incorporation of electron-withdrawing or lipophilic groups significantly enhance biological activity. Several compounds demonstrated potent inhibitory effects in the submicromolar range, while others exhibited dual or multi-target activity against key oncogenic pathways, including EGFR, AKT, ERK, and GSK3. Notably, fused triazole hybrids and multi-target-directed ligands showed improved anticancer activity across various cancer cell lines. Despite promising in vitro results, challenges such as isoform selectivity, toxicity, and pharmacokinetic limitations remain to be addressed. Overall, triazole-based hybrids represent a promising class of compounds for anticancer drug development, and further structure-guided optimization and in vivo studies are essential to facilitate their clinical translation.
Keyword:
MAP kinase; 1,2,3-triazole; 1,2,4-triazole; Anticancer agents; Structure-activity relationship (SAR); Kinase inhibitors
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