Development of small molecule inhibitors as anti-inflammatory agents and antidotes for arsenicals

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Arsenicals cause rapid, severe and painful inflammatory and blistering responses in the skin. The available medical countermeasures against arsenical-induced toxicity are not effective due to toxicity and a low therapeutic index. Hence, there is a demand for the development of more effective and less toxic antidotes for arsenicals. Developing hybrid inhibitors of bromodomain-containing protein 4 (BRD4) which are responsible for the regulation of inflammatory genes, receptor-interacting protein kinase-3 (RIP3, or RIPK3), a central player in necroptosis, and interleukin-6 (IL-6) would be an effective and efficient treatment to attenuate arsenical-induced inflammation. We have identified three potent inhibitors, SRI-43887, SRI-47362 and SRI-47561 of BRD4, RIPK3 and IL6. For example, SRI-43887 exhibited significant activity in vivo against phenylarsine oxide (PAO) and arsenicals (Lewisite)-induced mice. Continued optimization of these compounds will lead to the identification of a potential preclinical candidate(s) for the treatment of cutaneous injuries associated with arsenicals. To achieve this goal, we will (i) utilize molecular modeling to design and synthesize analogs of these three lead compounds and test in vitro for BRD4, RIPK3 and IL6 inhibitory activity; (ii) evaluate select compounds for cytotoxicity and in vitro drug-like properties (solubility, metabolic stability, log D, permeability); (iii) determine the in vivo pharmacokinetic profile (bioavailability and half-life); and (iv) perform in vivo studies on select compounds against PAO and Lewisite to determine the efficacy of these compounds. These goals will be accomplished through a collaborative effort involving a team with extensive experience in drug design, medicinal chemistry, computational chemistry, biological assays, pharmacokinetics, molecular biology and drug development.