Drug Delivery Strategy Exploiting Amino Acid Prodrugs: Improving Oral Bioavailability and Overcoming Nonlinear Pharmacokinetic Challenges Following Dose Escalation of a CK2 Inhibitor with Poor Solubility

Dissolution-limited absorption remains a major barrier to oral delivery of kinase inhibitors. BMS-135, a potent pan-CK2 inhibitor with robust antitumor efficacy, exhibited poor aqueous solubility (<1 μg/mL) that translated to low oral bioavailability (rat: <3%) and pronounced nonlinear pharmacokinetics following dose escalation─limitations unresolvable by precipitation-resistant solution formulations alone. To address this, we explored amino acid ester prodrugs designed to enhance intestinal solubility. Structure–property analysis demonstrated that polybasic side chains sustaining protonation at intestinal pH were critical for solubility enhancement. The l-lysine ester prodrug (12b) markedly improved solubility (pH 6.5: >1000 μg/mL) and delivered a 25-fold improvement in systemic exposure (F = 64.6%) with improved dose proportionality. Mechanistic investigation via portal vein cannulation revealed predominant intestinal first-pass bioconversion, explaining the minimal systemic prodrug exposure. These findings position amino acid prodrugs as a practical, low-risk strategy for unlocking oral bioavailability of dissolution-limited kinase inhibitors, offering broad applicability in contemporary drug discovery and development.