BMS-135 / BMS - LARVOL DELTA

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. (PubMed, J Med Chem) - "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...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."

Journal • PK/PD data • Oncology

Discovery of BMS-159, an Orally Active Imidazotriazine Pan-CK2 Inhibitor for the Treatment of Cancer. (PubMed, ACS Med Chem Lett) - "Iterative SAR optimization mitigated hERG liability by modulating distal basicity and enhanced metabolic stability via a C8 N-ethyl substitution that blocked N-dealkylation, delivering BMS-135 as a sub-nanomolar CK2 inhibitor with favorable ADMET properties and robust antitumor efficacy across xenograft and patient-derived xenograft models. Subsequent pharmaceutical optimization through a prodrug strategy afforded BMS-159, which markedly improved solubility and enabled oral delivery of the parent with acceptable bioavailability and pharmacokinetic properties suitable for further development."

Journal • Oncology

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. (PubMed, J Med Chem) - "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."

Journal • Oncology