Abstract B055: Development of a novel kinesin KIF20A inhibitor that selectively blocks aggressive prostate cancer growth

Abstract Discovering new therapies for castration-resistant prostate cancer (CRPC) as well as defining mechanisms underlying progression from androgen-dependent (AD) PC to CRPC are major clinical priorities. We previously established that the kinesin-6 family protein KIF20A is necessary and sufficient for CRPC development in cell- and animal-based models. Furthermore, patient data shows that KIF20A expression is higher in advanced PC stages and its expression is associated with worse tumor grade and shorter progression-free survival. KIF20A has well described roles in mitosis through regulation of microtubule bundling and organization of the central spindle and in the regulation of protein transport via vesicle trafficking. Additionally, KIF20A has distinct structural features and a unique mode of interacting with microtubules and ATP compared to other kinesins, allowing the selective targeting of KIF20A with a small molecule inhibitor, paprotrain. We found that while paprotrain reduces CRPC cell proliferation in vitro at submicromolar concentrations that spare non-tumorigenic cells, this KIF20A inhibitor has poor in vivo bioavailability. To overcome this deficiency that precludes in vivo pre-clinical efficacy studies, we developed 17 novel small molecules (UMF series) based on the paprotrain chemotype through iterative medicinal chemistry. We screened these compounds for selective growth inhibition of CRPC vs non-tumorigenic cells and by biochemical target engagement assays that measure microtubule-activated ATPase activity of purified KIF20A motor domain. We selected UMF-607, which demonstrated favorable stability in human and mouse microsomes, superior potency, and excellent drug-like features including good ADME properties after in vivo oral administration. Furthermore, UMF-607 showed no acute toxicity in mice receiving a high dose (300 mg/kg). Structure-based docking simulations at the KIF20A allosteric pocket showed that UMF-607 is bound with predicted high affinity. To complement planned in vivo preclinical CRPC xenograft efficacy studies, we conducted a genome-wide CRISPR drop-out screen and mass spec-based proteomics of AD LNCaP cells that acquired castration-resistant growth after ectopic expression of KIF20A. These studies will define mechanism(s) and potential biomarkers of sensitivity to KIF20A inhibition and will provide a basis for identification of patients most likely to respond to KIF20A inhibition. Citation Format: Morgan V. Pantone, Benjamin Pomeroy, Nahuel Peinetti, Viraj R. Sanghvi, Zhipeng Meng, Zoe Kaegi, Joey Schulz, Stephan Schürer, Yangbo Feng, Kerry L. Burnstein. Development of a novel kinesin KIF20A inhibitor that selectively blocks aggressive prostate cancer growth [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr B055.