Targeting SH2 domains with new chemical approaches and technologies
SH2 domains are critical for regulating the location and activity of proteins and play a key role in cellular signal transduction that, when abnormal, drives certain inflammatory disorders and cancers. They are small modules found in many proteins that mediate protein-protein interactions by binding to phospho-tyrosine containing motifs. There are 120 SH2 domains identified in humans.1
Discovered over 30 years ago, SH2 domains have been widely recognized as attractive drug targets in many disease pathways.
However, until recently, efforts to develop drug-like compounds to inhibit their function have been unsuccessful, and SH2 domains therefore have been considered undruggable.
Recludix’s SH2-focused platform integrates new chemical approaches and technologies to overcome this challenge, enabling the successful development of potent, selective, and drug-like SH2 domain inhibitors.
By directly engaging the active site, Recludix’s orthosteric SH2 domain inhibitors provide selective, potent, durable, and reversible inhibition. In contrast, allosteric inhibitors bind indirectly and may achieve less robust target engagement. Protein degraders remove the entire protein and thereby have greater potential for off-target effects and may unnecessarily impact cellular homeostasis.
Recludix leverages a validated prodrug mechanism to enable the efficient delivery and sustained concentrations of the active drug, enhancing target coverage. The prodrug is designed to optimize oral bioavailability and engineered for optimal plasma stability and efficient delivery to target tissues. This prodrug strategy has been validated by multiple available therapies, benefiting millions of patients worldwide.
There are numerous proteins implicated in disease pathology that have SH2 domains. Recludix’s initial programs are focused on the signal transducer and activator of transcription 6 (STAT6) protein found within the Janus kinase (JAK)/STAT signaling pathway, as well as Bruton’s tyrosine kinase (BTK) protein.
1. Liu BA et al. Molecular Cell, 22(6), 851–868.
Inhibiting STAT
JAK/STAT signaling pathways play a privileged role in the immune system, regulating the growth, differentiation, and activity of many types of immune cells. JAK/STAT pathways are abnormally activated in many inflammatory diseases as well as many cancers of the immune system. Targeting JAK/STAT pathways to treat inflammatory diseases and cancer has been clinically validated as an effective strategy by the success of JAK and TYK2 kinase inhibitors.
STAT proteins are found downstream in the JAK/STAT pathway, and therefore selective STAT inhibitors are predicted to be more targeted agents with fewer side effects. STAT proteins are both signaling proteins and transcription factors. They are phosphorylated, and thereby activated, by JAK family kinases in response to cytokine stimulation. Upon activation, STAT proteins dimerize and translocate to the nucleus, where they activate transcriptional programs that drive cell growth, differentiation, and function. Each of the seven STAT proteins (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6) contain an SH2 domain that mediates the two activities required for STAT proteins to act as transcription factors – their activation by cytokine stimulation and their dimerization. The inhibition of SH2 domains therefore interferes with STAT protein activity at multiple levels and provides an efficient and selective means to inhibit JAK/STAT signaling.
Inhibiting BTK
BTK is a signaling protein that is part of the tyrosine-protein kinase (TEC) family and plays an important role in the function and activation of B cells and myeloid cells.
BTK inhibitors that are approved to treat B-cell malignancies target the catalytic tyrosine kinase domain. Because other proteins’ kinase domains share close homology to BTK, it has been challenging to develop a highly specific BTK kinase inhibitor.
Recludix’s approach to drugging BTK is through inhibiting the SH2 domain, not the kinase domain, which enables a higher degree of specificity. Additionally, by blocking the SH2 domain, Recludix’s compounds inhibit the formation of the BTK pro-inflammatory complex, thereby inhibiting the scaffolding function of BTK.