Targeting Pyruvate Carboxylase by a Small Molecule Suppresses Breast Cancer Progression

Abstract

Rapid metabolism differentiates cancer cells from normal cells and relies on anaplerotic pathways. However, the mechanisms of anaplerosis‐associated enzymes are rarely understood. The lack of potent and selective antimetabolism drugs restrains further clinical investigations. A small molecule ZY‐444 ((N4‐((5‐(4‐(benzyloxy)phenyl)‐2‐thiophenyl)methyl)‐N2‐isobutyl‐2,4‐pyrimidinediamine) is discovered to inhibit cancer cell proliferation specifically, having potent efficacies against tumor growth, metastasis, and recurrence. ZY‐444 binds to cellular pyruvate carboxylase (PC), a key anaplerotic enzyme of the tricarboxylic acid cycle, and inactivates its catalytic activity. PC inhibition suppresses breast cancer growth and metastasis through inhibiting the Wnt/β‐catenin/Snail signaling pathway. Lower PC expression in patient tumors is correlated with significant survival benefits. Comparative profiles of PC expression in cancer versus normal tissues implicate the tumor selectivity of ZY‐444. Overall, ZY‐444 holds promise therapeutically as an anti‐cancer metabolism agent.

Impaired G2/M cell cycle arrest induces apoptosis in pyruvate carboxylase knockdown MDA-MB-231 cells

“…Our finding that knocking down of PC expression in MDA-MB-231 cells triggers programmed-cell death is well-supported by the very recent study. Li et al [ 27 ] showed that inhibition of PC activity with small molecule, ZY-444 in MDA-MB-231 cells inhibits their growth via caspase-3-dependent apoptosis.…”

Pyruvate carboxylase and cancer progression

“…Despite this detailed knowledge of the mechanisms and regulation of PC activity, there is a paucity of small molecules capable of target-specific inhibition of the enzyme. A recent study developed ZY-444, a small molecule which appears to bind to PC and inhibit enzymatic activity [ 89 ]. The exact binding mode of ZY-444 to PC was not determined, and several off-target binding proteins were identified.…”

Identification of Significant Genes and Therapeutic Agents for Breast Cancer by Integrated Bioinformatics

“…BP analysis in GO annotation indicated that the 10 signi cant genes are mainly enriched in the Wnt signaling pathway, which plays an important role in the occurrence and development of many cancers. Inhibiting this pathway can suppress breast cancer growth and metastasis [45][46][47]. MF analysis of GO suggested that the DEGs were most signi cantly enriched in functions related to oxidoreductase activity.…”