– Pioneering compounds believed to be the first orally administered reversible inhibitors to bind to and inhibit the SH2 domain potently and selectively
– Proprietary STAT3 inhibitors are differentiated in several ways from alternative approaches, including potency, selectivity, reversibility and oral bioavailability
SAN DIEGO, CA, October 17, 2023 – Recludix Pharma, a leader in platform approaches to discover inhibitors of challenging targets for inflammatory disease and cancer, announced that in a presentation given today titled “Drugging the Undruggable,” Recludix’s senior vice president of biology, Paul Smith, Ph.D., discussed the first application of the company’s platform capabilities to target the Src Homology 2 (SH2) domain, as well as reviewed preclinical data on an early STAT3 inhibitor that was internally discovered through the platform. The presentation is available on the company’s website under the section titled “Events.”
“We have had tremendous success in developing oral STAT inhibitors by targeting the SH2 domain, which has been previously considered undruggable,” said Nancy Whiting, PharmD, CEO of Recludix. “In this presentation, we highlight data from one of our earlier STAT3 discovery compounds showing its highly selective STAT3 inhibition with demonstrated potency in biochemical and cellular assays. We have continued to refine our lead STAT3 inhibitors and are in the final stages of confirming a STAT3 development candidate to move into clinical testing. We believe this could be a first- and best-in-class approach to selectively inhibit Th17-driven inflammatory diseases, such as psoriasis, rheumatoid arthritis, ulcerative colitis and Crohn’s disease.”
Recludix has generated potent and selective small molecule STAT3 inhibitors for Th17-driven inflammation. In T cell functional assays, Recludix’s STAT3 inhibitor potently and selectively impaired the Th17 phenotype, while still enabling the T cell to continue to perform robustly against viruses, bacteria, extracellular pathogens, and parasites. This is in contrast to the family of JAK or TYK2 inhibitors, which can be associated with changes in immune surveillance and hematopoiesis, leading to dose limiting safety concerns. Data demonstrate that targeting STAT3 spares interferon-driven anti-viral gene transcription and avoids STAT5 signaling, which is important for hematologic homeostasis and is differentiated from JAK/TYK2 inhibition.
In a preclinical model of multiple sclerosis, proof-of-concept was established that STAT3 inhibition modulates in vivo Th17 diseases as measured by mean clinical score compared to vehicle control, exhibiting greater preclinical disease control than the JAK inhibitor baricitinib. Activity for STAT3 was found to be dose-dependent in both prophylactic and therapeutic preclinical models. Selective STAT3 inhibition was also evaluated in an imiquimod-induced (Th17-dependent) model of psoriasis which demonstrated that STAT3 inhibition modulates disease as measured by the PASI score and skin thickness, and it does so comparably to a supra-maximal efficacious dose of the JAK inhibitor tofacitinib (30 mg/kg).
The interleukin cytokines IL-23 and IL-6 signal through STAT3 and promote the generation and function of pathogenic T helper type-17 (Th17) cells, a type of immune cell that is pro-inflammatory. Th17 cells are considered pivotal players in certain inflammatory diseases, including rheumatoid arthritis, psoriasis, inflammatory bowel disease and others. Inhibiting STAT3 can also offer potential efficacy beyond Th17 / IL-17 driven diseases in clinical indications where blocking the IL-6 pathway is clinically validated. Furthermore, clinical trials inhibiting oncostatin M (OSM) and IL-22, both STAT3 dependent cytokines, have been reported as efficacious in inflammatory disease.
A selective, oral STAT3 inhibitor has potential to replace JAK/TYK2 inhibitors and biologics for multiple inflammatory diseases.
STAT3 inhibitors may also have significant opportunity in cancer settings, as STAT3 is activated in greater than 70% of human cancers.
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 and founding scientific team members of Seagen and Blueprint Medicines. 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, as well as numerous cancer types, such as multiple leukemias and lymphomas. The company has a strategic partnership with Sanofi for the development and commercialization of a STAT6 inhibitor. Recludix is also advancing STAT3 inhibitors for Th17-mediated I&I diseases and oncology indications, as well as additional programs. For more information, please visit the company’s website at https://recludixpharma.com.