Unlocking the Potential of SH2 Domain‑Targeted Therapies
Recludix’s discovery platform integrates custom designed DNA-encoded libraries (DELs), massively parallel determination of structure activity relationships (SAR), structure-based design, and a first-in-class SH2 family-wide screening tool that drives selectivity and enables opportunistic target hopping.
Recludix is employing this platform approach first for the discovery of SH2 domain inhibitors that have favorable drug-like properties for the development of medicines against inflammatory diseases and cancer. Key features of this integrated platform also apply seamlessly to non-SH2 domain targets.
Platform Synergistically Integrates Multiple Technologies and Expertise
Custom-Designed DNA Encoded Libraries (DELs)
Recludix designs and tests custom DELs specifically tailored to broadly target SH2 domains (Discovery DELs) or to target specific SH2 domains and sub-families (SAR DELs). DEL design is an iterative process that synergizes with data from ongoing structure-based design, medicinal chemistry, prior DEL data, and SH2 family and sub-family selectivity profiling (see below). The DELs are designed to be both drug-like and to satisfy the unique features of SH2 binding sites.
Custom DELs are screened using proprietary approaches developed at Recludix that allow not only for the identification of novel chemical matter, but also for rapid, massively parallel, early SAR elucidation. In addition, DEL data, combined with structural biology (see below), has identified both novel inhibitor binding modes and cryptic SH2 domain affinity pockets. Using Recludix’s novel DEL selection designs and data analysis methods, quantitative SAR and selectivity information are obtained directly from primary screening results, often without the need for prolonged cycles of off-DNA synthesis. The DEL data therefore provide a jump-start for further compound optimization by traditional medicinal chemistry and structure-based design approaches.
Selectivity and Target Hopping
Selectivity is a critical consideration in drug development. Recludix has developed a large, first in class panel of SH2 domain assays covering more than 75 percent of the 120 human SH2 domains to assess family-wide cross-reactivity of compounds. This profiling panel also enables Recludix to opportunistically identify inhibitors for additional high value SH2 domains of interest (target hopping). Most compounds generated at Recludix during medicinal chemistry campaigns are screened against this large panel, and more than 250,000 interactions have been measured to date, enabling Recludix to have unprecedented insights into SH2 domain structure-selectivity relationships, while assuring that Recludix’s programs yield inhibitors confirmed to be selective.
Crystallography and Structure-Based Design
Recludix has established proprietary high-resolution small molecule co-crystallography systems that enable rapid data generation to inform new molecular design ideas for SH2 domain family members that have traditionally been challenging targets for structural biology. The enablement of structure-based drug design has resulted in a deep understanding of critical binding features that drive potency and selectivity, and have guided the design of custom Discovery and SAR DELs.