Recludix Unveils First BTK SH2 Domain Inhibitor

Image Credit: © DermNet

Bruton’s tyrosine kinase (BTK) is a critical regulator of B cell receptor (BCR) and Fc receptor signaling in B cells and mast cells. Traditional BTK inhibitors (TKIs) that target the ATP-binding kinase domain have achieved therapeutic benefit in several immune-mediated diseases. However, clinical efficacy has often been limited by transient target inhibition and significant off-target effects, including platelet dysfunction due to TEC kinase inhibition.¹ Recludix Pharma has taken a differentiated approach by targeting the SH2 domain of BTK, aiming to achieve deep, durable pathway inhibition with significantly improved selectivity. Recent research presented at the 2025 Society for Investigative Dermatology (SID) Annual Meeting demonstrates the discovery of a novel class of BTK SH2 domain inhibitors (BTK SH2i) that exhibit potent, selective, and durable inhibition of BTK signaling.²

Methods

The company’s SH2 domain discovery platform combines:

• Custom DNA-encoded libraries (DELs)
• SH2-targeted crystallographic structure-guided design
• Proprietary biochemical screening assays
• A prodrug delivery modality to enhance intracellular exposure

This workflow yielded highly selective SH2 inhibitors with biochemical potency (BTK Kd = 0.055 nM), minimal cytotoxicity (>10,000 nM EC50 in Jurkat cells), and exceptional SH2ome selectivity (>8000-fold over off-target SH2 domains).

Results

Selectivity and Kinome Profiling

Recludix’s BTK SH2i demonstrated best-in-class selectivity, exceeding even the most selective kinase domain inhibitors. Unlike current BTK TKIs, SH2i compounds avoided off-target inhibition of TEC kinase, reducing the potential for adverse effects such as platelet dysfunction. Kinase domain tree analysis showed a sharp contrast in off-target activity, with BTK SH2i showing superior specificity.

Cellular Assays

In vitro studies showed that BTK SH2i robustly inhibited SH2-dependent pERK signaling and suppressed downstream CD69 expression in B cells and TMD8 lymphoma cells. These results were consistent across multiple compound concentrations, indicating effective disruption of proximal BTK signaling.

Pharmacokinetics and Target Engagement

Following intravenous dosing in dogs, the prodrug achieved sustained intracellular concentrations of BTK SH2i in peripheral blood mononuclear cells (PBMCs) over 48 hours. This translated into dose-dependent and prolonged BTK target engagement, as shown in both pharmacokinetic and pharmacodynamic profiles.

CSU Preclinical Model

In a mouse model of OVA-induced CSU, a single prophylactic dose of BTK SH2i led to a significant, dose-dependent reduction in skin inflammation. Compared to remibrutinib and ibrutinib, BTK SH2i showed greater suppression of vascular leakiness and inflammatory cell infiltration. This suggests a superior ability to maintain functional pathway inhibition in vivo.

Discussion

Recludix Pharma's strategy to target the SH2 domain with small-molecule prodrugs represents a new therapeutic avenue for immunological diseases. According to Ajay Nirula, MD, PhD, EVP and Head of R&D at Recludix, this approach addresses key limitations of kinase-targeted BTK therapies—namely, poor durability and off-target effects. SH2i compounds provide a more selective, durable mechanism of action that could benefit patients with diseases such as CSU and multiple sclerosis.

“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,” Nirula said in a news release. “The clinical efficacy of BTK inhibitors that target the kinase domain is often compromised by the inability to maintaindeep 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 optionfor immunological diseases such as CSU and multiple sclerosis.”

Moreover, the avoidance of TEC kinase inhibition by BTK SH2i may reduce the bleeding risks associated with kinase domain-targeted therapies, further enhancing clinical appeal.

Conclusion

Recludix Pharma has developed the first known inhibitors of the BTK SH2 domain, introducing a novel and highly selective approach to modulate BTK-driven immune signaling. The preclinical data presented at SID 2025 demonstrate strong potency, exceptional selectivity, durable pathway inhibition, and efficacy in a CSU disease model. These findings support further clinical development of BTK SH2i for B cell and mast cell-mediated diseases.

References

1. Garg N, Padron EJ, Rammohan KW, Goodman CF. Bruton's tyrosine kinase inhibitors: The next frontier of B-cell-targeted therapies for cancer, autoimmune disorders, and multiple sclerosis. J Clin Med. 2022 Oct 18;11(20):6139. doi: 10.3390/jcm11206139. PMID: 36294458; PMCID: PMC9604914.
2. Recludix Pharma presents preclinical data on first-in-class BTK SH2 domain inhibitor demonstrating powerful BTK inhibition, exceptional selectivity, and encouraging efficacy in a model of chronic spontaneous urticaria. News release. BioSpace. Published May 8, 2025. Accessed May 14, 2025. https://www.biospace.com/press-releases/recludix-pharma-presents-preclinical-data-on-first-in-class-btk-sh2-domain-inhibitor-demonstrating-powerful-btk-inhibition-exceptional-selectivity-and-encouraging-efficacy-in-a-model-of-chronic-spontaneous-urticaria