Enhancing the Oral Bioavailability of a Poorly Soluble Pan-CK2 Kinase Inhibitor: Leveraging a Phosphate Prodrug Strategy to Overcome Dissolution-Limited Absorption and Improve Systemic Exposure during Dose Escalation

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.