Novel inhibitors of the scaffolding function of BTK selectively and potently block BTK signaling and are efficacious in preclinical models of chronic spontaneous urticaria

Summary: BTK signaling in multiple immune cell types is important in immunological diseases such as chronic spontaneous urticaria (CSU), rheumatoid arthritis, and multiple sclerosis. BTK supports pro-inflammatory signaling downstream of the Fc receptor and B cell receptor through formation of a signaling complex dependent on the BTK SH2 domain. Achieving clinical efficacy with BTK tyrosine kinase inhibitors (TKIs) has been compromised by failure to maintain deep and durable inhibition of BTK’s kinase activity. Additionally, off-target inhibition of TEC kinase has resulted in adverse events related to platelet dysfunction, such as bleeding and petechiae. Although no BTK inhibitors are yet approved for dermatologic diseases, LOU064 (remibrutinib, Novartis) has demonstrated Phase 3 efficacy in CSU and encouraging Phase 2 data in hidradenitis suppurativa. We have identified the first small molecule inhibitors targeting the previously undruggable SH2 domain of BTK (BTK SH2i). BTK SH2i are highly potent in biochemical (<1 nM) and cellular assays (<10 nM) and chemically differentiated from BTK TKIs. By inhibiting the scaffolding function of BTK, SH2 domain inhibitors potently block access to substrates such as PLCγ2 and inhibit downstream signaling and immune cell activation. Best-in-class selectivity is achieved for BTK over both safety-related off-targets (>85,000× over TEC) and the SH2ome (>5,000× over other SH2 domains). BTK SH2i prodrugs enable prolonged intracellular pharmacokinetics that achieve deep and durable target engagement in PBMCs for at least 48 hours. In a clinically-relevant mouse model of CSU, BTK SH2 inhibitors achieve efficacy equivalent to BTK TKIs. Selective, potent, and durable inhibitors of BTK’s scaffolding function have the potential to safely enable broader clinical efficacy in dermatologic disease. Mark A. Eckert¹, Ksenya Cohen-Katsnelson¹, Gizem Guzelsoy¹, Travis Grant¹, Jaime Rodriguez¹, Jeong-Ho Kim¹, Max Orr¹, Allen Sickmier¹, Giovanni Cianchetta¹, Neil Bifulco¹, Xia Tian¹, Brian Hodous¹, Paul Smith¹, Dan Treiber¹, Samuel K. Reznik¹ 1. Recludix Pharma Inc, San Diego, CA, United States. Translational Studies: Preclinical