VYNE Therapeutics Inc. announced the selection of a development candidate for its oral BD2-selective bromodomain and extra-terminal (“BET”) inhibitor program, VYN202, for the treatment of immuno-inflammatory conditions. The lead candidate was selected by VYNE from a library of BD2-selective BET inhibitors that VYNE exclusively licensed from Tay Therapeutics following the receipt of a robust package of preclinical data, including encouraging results from well-validated animal models in various autoimmune disorders. VYNE also obtained rights to several other BD2-selective BET inhibitor compounds with attractive molecular profiles that the Company may develop, at its discretion, in the future.

VYN202 targets BET proteins that play key roles in regulating gene transcription via epigenetic interaction (“reading”) with specific chemical motifs on H3 and H4 histone N-terminal tail domains that extend beyond a nucleosome unit. As epigenetic readers, BET proteins are super-enhancers of gene transcription that drive the hyperactive production of many pro-inflammatory proteins that characterize autoimmune and autoinflammatory diseases. Recent research has highlighted BET proteins as important contributors in regulating both B cell and T cell activity and, in preclinical models, BET inhibitors have demonstrated the potential to treat a range of immuno-inflammatory and fibrotic diseases.

Early generation systemic BET inhibitors that inhibit both the BD1 and BD2 domains of BET proteins (pan-BD BET inhibitors) have historically been associated with gastrointestinal and hematological toxicities, such as thrombocytopenia (low platelet counts) in clinical trials. BD1 functionality has been associated with the regulation of genes responsible for maintaining homeostatic cellular processing, and that selectively inhibiting BD1 or BD1 and BD2 may contribute to unwanted dose limiting toxicities. VYN202 is designed to be significantly more selective in inhibiting BD2 than BD1 with the objective of limiting the potential of similar safety concerns associated with earlier pan-BD BET inhibitors.

VYNE has initiated IND-enabling studies for VYN202 and intends to submit an IND by year-end. Under VYNE's license agreement with Tay, VYNE has exclusive worldwide rights to the compounds in its InhiBET platform, including VYN202, for all human disease applications. Gilan et al, Science., 2020 April 24; 368(6489): 387; Kawahito et al, Pulm.

Pharma. & Therp., 2021; 70:102057; Sun et al, Front. Pharmacol., 2021; 11:621093 and Faivre et al, Nature, 2020; 578:306.