Pena, M. M. | bioRxiv Science

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↗

bioRxiv2023

Genetic and functional diversity help explain pathogenic, weakly pathogenic, and commensal lifestyles in the genus Xanthomonas

The genus Xanthomonas has been primarily studied for pathogenic interactions with plants. However, besides host and tissue specific pathogenic strains, this genus also comprises nonpathogenic strains isolated from a broad range of hosts, sometimes in association with pathogenic strains, and other environments, including rainwater. Based on their incapacity or limited capacity to cause symptoms on the host of isolation, nonpathogenic xanthomonads can be further characterized as commensal and weakly pathogenic. This study aimed to understand the diversity and evolution of nonpathogenic xanthomonads compared to their pathogenic counterparts based on their co-occurrence and phylogenetic relationship and to identify genomic traits that form the basis of a life-history framework that groups xanthomonads by ecological strategies. We sequenced genomes of 83 strains spanning the genus phylogeny and identified eight novel species, indicating unexplored diversity. While some nonpathogenic species have experienced a recent loss of a type III secretion system, specifically, the hrp2 cluster, we observed an apparent lack of association of the hrp2 cluster with lifestyles of diverse species. We gathered evidence for gene flow among co-occurring pathogenic and nonpathogenic strains, suggesting the potential of nonpathogenic strains to act as a reservoir of adaptive traits for pathogenic strains and vice versa. We further identified traits enriched in nonpathogens that suggest a strategy of stress tolerance, rather than avoidance, during their association with a broad range of host plants.

ecology↗