Metastatic castration-resistant prostate cancer remains incurable regardless of recent therapeutic advances. Prostate cancer tumors display highly glycolytic phenotypes as the cancer progresses. Non-specific inhibitors of glycolysis have not been utilized successfully for chemotherapy, because of their penchant to cause systemic toxicity. This study reports the preclinical activity, safety, and pharmacokinetics of a novel small molecule preclinical candidate, BKIDC-1553, with antiglycolytic activity. We tested a large battery of prostate cancer cell lines for inhibition of cell proliferation, in vitro. Cell cycle, metabolic and enzymatic assays were used to demonstrate their mechanism of action. A human PDX model implanted in mice and a human organoid were studied for sensitivity to our BKIDC preclinical candidate. A battery of pharmacokinetic experiments, absorption, distribution, metabolism, and excretion experiments, and in vitro and in vivo toxicology experiments were carried out to assess readiness for clinical trials. We demonstrate a new class of small molecule inhibitors where antiglycolytic activity in prostate cancer cell lines is mediated through inhibition of hexokinase 2. These compounds display selective growth inhibition across multiple prostate cancer models. We describe a lead BKIDC-1553 that demonstrates promising activity in a preclinical xenograft model of advanced prostate cancer, equivalent to that of enzalutamide. BKIDC-1553 demonstrates safety and pharmacologic properties consistent with a compound that can be taken into human studies with expectations of a good safety margin and predicted dosing for efficacy. This work supports testing BKIDC-1553 and its derivatives in clinical trials for patients with advanced prostate cancer.
Molecular cancer therapeutics. 2024 Mar 20 [Epub ahead of print]
Takuma Uo, Kayode K Ojo, Cynthia C T Sprenger, Kathryn Soriano Epilepsia, B Gayani K Perera, Mamatha Damodarasamy, Shihua Sun, Soojin Kim, Hannah H Hogan, Matthew A Hulverson, Ryan Choi, Grant R Whitman, Lynn K Barrett, Samantha A Michaels, Linda H Xu, Vicky L Sun, Samuel L M Arnold, Haley J Pang, Matthew M Nguyen, Anna-Lena B G Vigil, Varun Kamat, Lucas B Sullivan, Ian R Sweet, Ram Vidadala, Dustin J Maly, Wesley C Van Voorhis, Stephen R Plymate
University of Washington, Seattle, United States., University of Washington, Seattle, WA, United States., University of Washington, Seattle, Washington, United States., Fred Hutchinson Cancer Center, Seattle, Washington, United States., Fred Hutchinson Cancer Center, Seattle, WA, United States.