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

  • J Med Chem. 2026 Jun 25;69(12):14836-14853. doi: 10.1021/acs.jmedchem.6c00912.
Murugaiah A M Subbaiah  1 ,  Thangeswaran Ramar  1 ,  Mathiazhagan Annadurai  1 ,  Arunachalam Arumugam  2 ,  Ramesh Samikannu  2 ,  Kurt Zimmermann  3 ,  Megha A Thakur  4 ,  Vinay K Holenarsipur  4 ,  Tarun Sharma  4 ,  Sheelendra Singh  4 ,  Shahe Mahammad  5 ,  Mary T Obermeier  6 ,  Srinivas Kasibhatla  1 ,  Natesan Murugesan  3 ,  Sridhar Desikan  5 ,  Sandhya Mandlekar  4 ,  Gerry Everlof  6 ,  Aberra Fura  6 ,  Ashok V Purandare  3
Affiliations
  • 1. Department of Medicinal Chemistry, Discovery & Development Sciences, Biocon-Bristol Myers Squibb Research and Development Centre, Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bengaluru 560099, India.
  • 2. Department of Chemical Synthesis, Discovery & Development Sciences, Biocon-Bristol Myers Squibb Research and Development Centre, Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bengaluru 560099, India.
  • 3. Department of Medicinal Chemistry, Discovery & Development Sciences, Bristol Myers Squibb Research and Development, PO Box 4000, Princeton, New Jersey 08543-4000, United States.
  • 4. Department of Pharmaceutical Candidate Optimization, Discovery & Development Sciences, Biocon-Bristol Myers Squibb Research and Development Centre, Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bengaluru 560099, India.
  • 5. Department of Biopharmaceutics, Discovery & Development Sciences, Biocon-Bristol Myers Squibb Research and Development Centre, Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bengaluru 560099, India.
  • 6. Department of Pharmaceutical Candidate Optimization, Discovery & Development Sciences, Bristol Myers Squibb Research and Development, PO Box 4000, Princeton, New Jersey 08543-4000, United States.
PMID: 42258774 DOI: 10.1021/acs.jmedchem.6c00912
Abstract

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.

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