Recludix Pharma has announced promising preclinical data for its first-in-class Bruton's tyrosine kinase (BTK) SH2 domain inhibitor, demonstrating powerful BTK inhibition with exceptional selectivity and encouraging efficacy in models of chronic spontaneous urticaria (CSU). The data was presented at the Society for Investigative Dermatology (SID) annual meeting in San Diego.
The company's novel approach targets the SH2 domain of BTK rather than the kinase domain, which is the target of conventional BTK inhibitors. This strategy has yielded a compound with remarkable selectivity and potent inhibition of the BTK pathway, potentially addressing significant limitations of existing therapies.
"We have developed the first known BTK SH2 domain inhibitor, and have shown preclinically that it was effective at reducing skin inflammation in a model of CSU and has exquisite target selectivity not matched by other BTK-targeting therapies," said Ajay Nirula, M.D. Ph.D., executive vice president and head of research and development of Recludix.
Dr. Nirula highlighted a key advantage of their approach: "The clinical efficacy of BTK inhibitors that target the kinase domain is often compromised by the inability to maintain deep inhibition of the BTK pathway. Additionally, TKIs and kinase degraders can induce toxicities related to off-target kinase inhibition, such as platelet dysfunction."
Superior Selectivity Profile
Preclinical studies demonstrated that Recludix's BTK SH2 domain inhibitor (BTK SH2i) achieved best-in-class selectivity for BTK, surpassing even the most selective BTK tyrosine kinase inhibitors (TKIs) currently available. Importantly, broader off-target profiling across the kinome revealed that while current BTK TKIs and degraders showed off-target inhibition of TEC—a kinase associated with platelet dysfunction—Recludix's BTK SH2i did not exhibit this liability.
This exceptional selectivity profile suggests the potential for improved safety compared to existing BTK inhibitors, which often face dose-limiting toxicities due to off-target effects.
Robust Efficacy in Preclinical Models
The potency of the BTK SH2i was demonstrated across multiple preclinical assays and models:
- In vitro studies showed robust inhibition of proximal SH2-dependent phosphorylation (pERK) signaling and downstream immune cell activation (B cell CD69 expression)
- In vivo administration enabled deep, durable, and dose-dependent target engagement
- In a clinically relevant model of CSU, a dose-dependent reduction in skin inflammation was observed following a single dose
These findings suggest that a highly-selective BTK SH2i has the potential to provide maximal efficacy through deep and durable inhibition of the BTK pathway while minimizing the off-target safety risks associated with kinase-targeted agents.
Targeting BTK for Inflammatory Diseases
BTK plays a crucial role in both innate and adaptive immune responses, including the differentiation and activation of B cells and myeloid cells. It represents a promising target for treating autoimmune diseases where B cell overactivation and self-antibody generation contribute to disease pathogenesis.
Additionally, BTK is involved in inflammatory cytokine production, making it relevant to chronic inflammatory disorders. Recludix believes their approach of inhibiting BTK via the SH2 domain with a small molecule prodrug represents "an exciting potential treatment option for immunological diseases such as CSU and multiple sclerosis."
Beyond CSU and multiple sclerosis, BTK inhibitors could potentially address a range of autoimmune and inflammatory conditions, including graft-versus-host disease, systemic lupus erythematosus, Sjögren's disease, and pemphigus vulgaris.
Recludix's Innovative Platform
This breakthrough builds on Recludix's unique drug discovery platform, which integrates custom-generated DNA-encoded libraries, massively parallel determination of structure-activity relationships, and proprietary screening tools to ensure selectivity.
The company is employing this approach primarily in developing SH2 domain inhibitors. Beyond BTK, Recludix's programs include STAT (signal transducer and activator of transcription) protein inhibitors for inflammatory diseases such as rheumatoid arthritis, asthma, atopic dermatitis, and inflammatory bowel disease. The company has established a strategic partnership with Sanofi for the development and commercialization of a STAT6 inhibitor.
The poster presentation, titled "Novel Inhibitors of the BTK SH2 Domain Selectively and Potently Block BTK Signaling and are Efficacious in Preclinical Models of Chronic Spontaneous Urticaria," was presented at the SID annual meeting on May 8, 2025.
