Murugaiah A. M. Subbaiah, Naveen Manjunath, Thangeswaran Ramar, Mathiazhagan Annadurai, Naveen Kumar Dhondi, Tarun Kumar Sharma, Sheelendra Pratap Singh, Megha Thakur, Priyadeep Bhutani, Shahe Mahammad, Srinivas Rao Kasibhatla, Sridhar Desikan, Kurt Zimmermann, Xiaopeng Sang, Gerry Everlof, Mary T. Obermeier, Aberra Fura, Ashok V. Purandare
BMS-135, a preclinical casein kinase 2 (CK2) inhibitor, demonstrated subnanomolar potency, robust cellular antiproliferative activity, and pronounced antitumor efficacy in xenograft models. However, its poor solubility posed significant challenges for oral delivery, leading to low oral bioavailability when administered as a solid suspension. Solution formulations improved exposure at lower doses but failed to support dose escalation, resulting in nonlinear pharmacokinetics and diminished bioavailability at higher doses. To overcome these formulation limitations, this study describes the design and synthesis of direct and linker-enabled phosphate prodrugs, resulting in significantly enhanced solubility and improved oral bioavailability up to 14-fold. PK analyses revealed that systemic exposure was governed by both phosphate cleavage and intermediate hydrolysis rates, with steric factors critically influencing enzymatic activation. These findings support the continued development of BMS-135 as an orally bioavailable anticancer therapeutic and highlight the strategic utility of phosphate prodrugs for facilitating the oral delivery of poorly soluble kinase inhibitors.