Drug Delivery Strategy Exploiting Amino Acid Prodrugs: Improving Oral Bioavailability and Overcoming Nonlinear...

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.