Evaluation of Pyrrolone‐Fused Benzosuberene MK2 Inhibitors as Promising Therapeutic Agents for HNSCC: In Vitro Efficacy, In‐Vivo Safety, and Pharmacokinetic Profiling

MAPKAPK2/MK2 is well implicated in the progression of Head and Neck Squamous Cell Carcinoma (HNSCC), and potent MK2-inhibitors are required to suppress its activity. Several MK2-inhibitors have been developed in recent years to combat its effects on cancer. However, inadequate solubility, insufficient cellular permeability, systemic toxicity-mediated side effects, and low bioavailability have severely impeded the advancement of MK2-inhibitors to clinical trials. This void necessitates research to develop less toxic and more bioavailable potent MK2-inhibitors in HNSCC. In the present article, we have evaluated the in-vitro efficacy, in-vivo single-dose acute toxicity, and in-vivo pharmacokinetic profiling of recently developed PfBS (pyrrolone-fused benzosuberene) MK2-inhibitor analogues against HNSCC. The PfBS MK2 inhibitor analogues impeded HPV+ and HPV- HNSCC cell proliferation and two-dimensional migration. Moreover, MK2-inhibitors lowered HNSCC cell clonogenic survival in a dose-dependent manner, significantly enhancing radiation-induced cell death via exerting radio-sensitization effects. Furthermore, γ-H2AX immunostaining revealed that PfBS analogues impaired DNA damage repair in HNSCC cells exposed to gamma radiation. In mice, PfBS MK2 inhibitors at 300 mg/kg were well-tolerated without any lethal effects. Pharmacokinetic studies showed that PfBS analogues exhibited rapid absorption (Tmax), adequate plasma concentration above the micromolar level (C0 or Cmax), limited tissue distribution (Vd), and faster elimination from the body (Cl). Overall, this study summarizes in-vitro efficacy, safety, and pharmacokinetics of developed MK2-inhibitors and opens doors for pharmacodynamics and mechanism of action study of most effective leads in HNSCC.