Novel anti-cancer compounds targeting cancer stem cells: mechanistic insights into mitophagy-associated cellular senescence and tumor suppression

Abstract

Cancer stem cell-like phenotypes contribute to tumor recurrence, metastasis and therapeutic resistance, creating a need for compounds that suppress tumor stemness while revealing new druggable vulnerabilities. This thesis investigates pleuromutilin-derived anticancer compounds targeting cancer stem cell-associated phenotypes, with a focus on the mechanism by which ZK-3-38-1 suppresses colorectal cancer progression.

Through phenotypic screening, chemical proteomics, target validation and functional studies, ZK-3-38-1 was identified as a bioactive compound that suppresses colorectal cancer cell proliferation, invasion and stemness-associated phenotypes. Mechanistic studies indicated that ZK-3-38-1 targets SLC25A5/adenine nucleotide translocase 2 (ANT2), leading to mitochondrial dysfunction, increased reactive oxygen species and induction of a senescence-associated phenotype. Unlike conventional senescence, ANT2 inhibition did not induce a strong canonical senescence-associated secretory phenotype (SASP). Further investigation suggested that ANT2 inhibition activates PINK1-dependent mitophagy, limiting mitochondrial DNA leakage and reducing cGAS–STING pathway activation. This phenotype was defined as mitophagy-associated cellular senescence (MiACS).

In colorectal cancer xenograft and patient-derived xenograft models, ZK-3-38-1 showed antitumor activity and enhanced the therapeutic effect of 5-fluorouracil. Structural optimization of the ZK-3-38-1 scaffold further identified Y7 as an optimized analogue with inhibitory activity against small cell lung cancer cells and xenograft growth. Overall, this thesis identifies ANT2 as a potential druggable vulnerability and proposes MiACS as a mechanism linking mitochondrial dysfunction, mitophagy and SASP-attenuated tumor suppression.

Date of Award	15 Nov 2026
Original language	English
Awarding Institution	University of Nottingham
Supervisor	Bencan Tang (Supervisor), Jonathan D. Hirst (Supervisor) & Michael J. Stocks (Supervisor)