— Bruton’s tyrosine kinase (BTK) SH2 inhibitor reduced skin inflammation in a clinically-relevant model of chronic spontaneous urticaria (CSU)
— BTK inhibition through the SH2 domain results in greater selectivity as compared to BTK tyrosine kinase inhibitors (TKIs) or degraders
SAN DIEGO, May 07, 2025 (GLOBE NEWSWIRE) — Recludix Pharma, a leader in the discovery of inhibitors of challenging targets for inflammatory disease, today announced data will be presented at the Society for Investigative Dermatology (SID) annual meeting in San Diego, CA, from an abstract titled, “Novel Inhibitors of the BTK SH2 Domain Selectively and Potently Block BTK Signaling and are Efficacious in Preclinical Models of Chronic Spontaneous Urticaria.” The data demonstrate that the company has identified potent BTK SH2 domain inhibitors (BTK SH2i) with durable pathway inhibition and notably high selectivity for BTK, representing an attractive therapeutic approach for B cell and mast cell-mediated inflammatory diseases.
“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. “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. We believe that our approach of inhibiting BTK via the SH2 domain with a small molecule prodrug can address these shortcomings and is an exciting potential treatment option for immunological diseases such as CSU and multiple sclerosis.”
The company’s BTK SH2i demonstrated best-in-class selectivity for BTK far greater than even the most selective BTK TKIs. Broader off-target profiling across the kinome confirmed that while current BTK TKIs and degraders showed off-target inhibition of TEC, which is associated with platelet dysfunction, Recludix’s BTK SH2i did not.
The potency of a BTK SH2i was shown across multiple preclinical assays and models. In vitro, a BTK SH2i robustly inhibited proximal SH2-dependent phosphorylation (pERK) signaling and downstream immune cell activation (B cell CD69 expression). In an in vivo model, the administration of a BTK SH2i enabled deep, durable, and dose-dependent target engagement. In an in vivo model of CSU, a dose-dependent reduction in skin inflammation was observed following a single dose of a BTK SH2i.
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.
| Poster Presentation Details: | |
| Title: | Novel Inhibitors of the BTK SH2 Domain Selectively and Potently Block BTK Signaling and are Efficacious in Preclinical Models of Chronic Spontaneous Urticaria |
| Poster Number: | LB1255 |
| Session: | Poster Session 1 |
| Date and Time: | Thursday, May 8, 2025; 4:30 p.m. – 6:00 p.m. PT |
About BTK
Bruton’s tyrosine kinase (BTK) is involved in both the innate and adaptive immune responses, including in the differentiation and activation of B cells and myeloid cells. It is a promising target for the treatment of autoimmune diseases where the overactivation of B cells and the generation of antibodies against self are part of the disease pathogenesis. BTK is also involved in the production of inflammatory cytokines. The overproduction of cytokines can result in chronic inflammation, a hallmark of inflammatory disorders. BTK inhibitors could be a valuable treatment option for multiple autoimmune and inflammatory diseases, such as chronic spontaneous urticaria, graft-versus-host disease, multiple sclerosis, systemic lupus erythematosus, Sjögren’s disease and pemphigus vulgaris, among others.
About Recludix
Recludix is a leader in developing platform approaches to discover potent and selective inhibitors of challenging protein targets. The company’s management team includes industry veterans with a track record of success, including former leaders of Seagen, Blueprint Medicines, and Lilly. Recludix has developed a unique drug discovery platform that integrates custom generated DNA-encoded libraries, massively parallel determination of structure activity relationships, and a proprietary screening tool to ensure selectivity. The company is employing this approach first in the development of SH2 domain inhibitors. Recludix’s most advanced programs are focused on STAT (signal transducer and activator of transcription) proteins where abnormal activation is found in inflammatory diseases, such as rheumatoid arthritis, asthma, atopic dermatitis, and inflammatory bowel disease. The company has a strategic partnership with Sanofi for the development and commercialization of a STAT6 inhibitor. Recludix is also advancing potential first-in-class BTK SH2 domain inhibitors for B cell or mast cell-driven I&I diseases, STAT3 SH2 domain inhibitors for Th17-mediated I&I diseases, as well as additional programs. Recludix was named a 2024 Fierce 15 biotech company. For more information, please visit the company’s website at https://recludixpharma.com.
Recludix Contacts
Matt Caldemeyer
Chief Business Officer
[email protected]
Alexandra Santos
[email protected]
Aljanae Reynolds
[email protected]
