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

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.

Grant Number: 7UG3AR083022-04
NIH Institute/Center: NIH
Principal Investigator: CORINNE AUGELLI-SZAFRAN