Integrated Pharmacogenomic and Structure-Guided Analyses Link LCC-10 (NSC765599) to an MMP-Associated Extracellular Matrix Regulatory Network in Leukemia

Le résumé fourni par la source

Leukemia progression is increasingly shaped by reciprocal interactions between leukemic cells and the bone marrow microenvironment, yet the extracellular regulatory networks associated with these interactions remain incompletely understood. Here, we investigated the biological context associated with the antileukemic activity of LCC-10 (NSC765599), a synthetic biphenyl benzamide derivative, using an integrated pharmacogenomic and structure-guided computational framework. Antiproliferative activity was first characterized using the NCI-60 screen and subsequently integrated with pharmacogenomic response similarity analysis, baseline transcriptomic profiling, similarity-based target prediction, systems-level network analysis, molecular docking, coarse-grained molecular dynamics simulations, comparative in silico ADMET evaluation, and zebrafish embryo developmental toxicity assessment. LCC-10 exhibited potent antiproliferative activity across leukemia cell lines, with submicromolar GI50 values in five of six models. Computational analyses converged on a matrix metalloproteinase (MMP)-associated extracellular matrix (ECM) regulatory network, with MMP2 and MMP9 among the recurrently implicated candidates. Structure-guided analyses suggested structural compatibility of LCC-10 with representative MMP catalytic domains but did not establish direct biochemical inhibition or target engagement. Comparative in silico ADMET analyses supported the predicted developability profile of LCC-10, whereas zebrafish embryo assays indicated concentration-dependent developmental tolerability within the tested range. Collectively, these findings associate LCC-10 with an MMP-associated ECM regulatory network in leukemia while defining this relationship as a hypothesis requiring direct experimental validation. This integrated framework provides a rationale for subsequent biochemical, target-engagement, and functional studies to clarify the molecular basis of LCC-10 activity.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.