Biology subjects

McInnes, C.

Publications and source records attributed to McInnes, C..

4 recordsLinked to original sources

bioRxiv2026

Lysyl oxidase drives ccRCC progression by coordinating HIF-2α transcription program with tumor microenvironment

Clear cell renal cell carcinoma (ccRCC) is driven by persistent HIF-2 transcription program initiated by VHL loss, yet molecular mediators sustaining this program are poorly defined. Using single-cell transcriptomics, we identified lysyl oxidase (LOX) as a driver of ccRCC progression, selectively enriched in a hypoxia/epithelial-mesenchymal transition (EMT) gene program associated with poor outcome. While LOX oxidizes and stabilizes HIF-2 by antagonizing HUWE1-mediated ubiquitination and degradation, thereby sustaining HIF-2-driven transcription in cancer cells, it also remodels extracellular matrix (ECM) and promotes angiogenesis in the tumor microenvironment (TME). Genetic or pharmacological inhibition of LOX destabilizes HIF-2, disrupts ECM, inhibits angiogenesis, and suppresses tumor initiation, growth, and metastasis in vivo. LOX inhibition enhances anti-angiogenic therapy response and remains effective in belzutifan-resistant HIF-2 G323E-mutant tumors. Nuclear LOX protein correlates with nuclear HIF-2 in high-grade patient tumors. Together, LOX coordinates HIF-2 transcription program with TME and is a therapeutic target in ccRCC.

cancer biology↗

bioRxiv2026

Abbapolin inhibitors of the PLK1 PBD as Prostate Cancer Therapeutics, in vivo activity and synergy with androgen therapy

Polo-like kinase 1 (PLK1) is an established therapeutic target in cancer; however, ATP-competitive kinase inhibitors have shown limited clinical success because of toxicity, acquired resistance, and incomplete inhibition of non-catalytic PLK1 functions. Targeting the Polo-box domain (PBD), which regulates PLK1 localization and substrate recognition, represents an alternative therapeutic strategy but has been hindered by the lack of selective, cell-active small molecules. Here, the optimization and biological characterization of abbapolins, a series of non-peptidic PLK1 PBD inhibitors developed using the REPLACE strategy are described. Structure-guided optimization and screening across the NCI-60 cancer cell panel identified compounds with preferential activity against prostate cancer cells. Proteomic analyses demonstrated that cellular sensitivity correlated with PLK1 protein abundance, supporting an on-target mechanism of action. Abbapolins directly engaged PLK1 in cells, induced selective degradation of endogenous PLK1, and suppressed long-term clonogenic growth. Lead compounds demonstrated favorable pharmacokinetic properties and significantly inhibited prostate tumor growth in xenograft models without detectable systemic toxicity. PLK1 abundance was significantly reduced in treated tumors and correlated with tumor response, identifying PLK1 degradation as a potential pharmacodynamic biomarker. Abbapolins also synergized with enzalutamide in castration- resistant prostate cancer cells, supporting their potential as combination therapies for advanced disease. Collectively, these studies establish selective inhibition of the PLK1 Polo-box domain as a viable therapeutic strategy, provide in vivo proof-of-concept for the REPLACE approach, and identify abbapolins as promising leads for advanced prostate cancer.

cancer biology↗

bioRxiv2024

Insights into the Structural Regulation of Polo-Like Kinase Activity using AlphaFold

The Polo Like Kinases including the major family member, PLK1 are key regulatory enzymes controlling the cell cycle and mitosis. PLK1 is associated with poor survival rates in cancer and has been extensively investigated as an oncology drug target. Each member of the Polo like kinase family (PLKs 1-5) have two subdomains with independent functions and include the well conserved N-terminal kinase domain (KD) and the C-terminal polobox domain (PBD). The PBD is involved in the recognition of substrates primed by other kinases and in the PLK1 context is responsible for subcellular localization to specific sites in the nucleus including centrosomes and kinetochores. While the phosphosubstrate recognition site in PLKs 1-3 is highly conserved, its role in PLKs 2 and 3 is not well characterized and phosphopeptides that inhibit PLK1 have dramatically lower affinity for PLKs 2 and 3. An additional role of the PBD is its ability through domain-domain interactions with the KD to regulate PLK1 activity by an autoinhibited state of PLK1, conceptually similar to that which occurs through other kinases. Other mechanisms regulating PLK activity include the interchange between monomeric and dimeric forms, which inhibit or activate PLK1 during the cell cycle. Furthermore, PLK1 may exist as heterodimers with PLK2 and/or PLK3 and thus play context dependent roles. Here, through the use of the AlphaFold (AF) algorithm, structural insights into regulation of activity of the PLK1 and other family members have been obtained. These include dramatically different tertiary arrangement of the individual domains in each individual PLK. Analysis of the domain-domain interactions, interdomain and intradomain loops in each PLK sheds light onto plausible mechanisms by which the activity of each PLK is regulated and provides insights into the selectivity of phosphopeptides. The results also suggest a mechanism for the heterodimerization of PLK1 and PLK2 which has been observed in the literature.

biochemistry↗

bioRxiv2023

CDK19 and CDK8 Mediator kinases drive androgen-independent in vivo growth of castration-resistant prostate cancer

Castration-resistant prostate cancer (CRPC) remains incurable due to its high plasticity. We found that Mediator kinases CDK8 and CDK19, pleiotropic regulators of transcriptional reprogramming, are differentially affected by androgen, which downregulates CDK8 and upregulates CDK19. Accordingly, expression of CDK8 decreases while CDK19 increases during prostate carcinogenesis, but both CDK19 and CDK8 are upregulated in metastatic CRPC. Genetic inactivation of CDK8 and CDK19 suppresses CRPC tumor growth in castrated male mice and renders CRPC responsive to androgen deprivation. Restoration of active CDK19 or CDK8 kinases reverses this phenotype, indicating that CRPC becomes dependent on Mediator kinase activity for in vivo growth under the conditions of androgen deprivation. Selective CDK8/19 inhibitors suppress androgen-independent growth of cell line-based and patient-derived CRPC xenografts, whereas prolonged inhibitor treatment induces tumor regression and even leads to cures. Mediator kinase activity was found to affect tumor and stromal gene expression preferentially in castrated mice, orchestrating castration-induced transcriptional reprogramming. These results warrant the exploration of Mediator kinase inhibitors for CRPC therapy.

cancer biology↗