Discovery life go com activate4/3/2024 ![]() HQ461 was identified through phenotype-based high-throughput small-molecule screening and found to possess potent cytotoxicity. In this study, we report the discovery and the mechanism of action of a new molecular glue HQ461. However, the rarity of molecular glues has limited their potential as a general strategy for drug development. For example, the compactness of the thalidomide scaffold allowed the development of bivalent proteolysis targeting chimeras to direct cereblon to degrade disease-relevant proteins ( Lu et al., 2015 Winter et al., 2015). Third, molecular glues possess favorable pharmacological properties to serve as drug candidates. Second, molecular glues can target transcription factors and splicing factors, by recognizing either relatively flat surfaces or disordered regions of these proteins ( Han et al., 2017 Krönke et al., 2014 Lu et al., 2014 Tan et al., 2007). Such unique binding characteristics can be explained by induced protein-protein interactions and pre-existing protein surface complementarity as revealed by structural analysis of molecular glue-bound protein complexes ( Bussiere et al., 2020 Du et al., 2019 Faust et al., 2020 Tan et al., 2007). First, molecular glues often bind to their target proteins with modest or even undetectable affinities, while enhanced affinities are usually observed once a regulatory protein is also present in the system ( Bussiere et al., 2020 Du et al., 2019 Faust et al., 2020). Several common themes have emerged from this limited set of molecular glues. More recently, indisulam and related anticancer sulfonamides were discovered to function by promoting the interaction between the splicing factor RBM39 and the E3 ubiquitin ligase DCAF15, resulting in the degradation of RBM39 to cause aberrant pre-mRNA splicing ( Han et al., 2017 Uehara et al., 2017). Similarly, the thalidomide class of immunomodulatory drugs binds to the E3 ubiquitin ligase cereblon and alters its substrate specificity to recognize and degrade several zinc finger transcription factors ( Ito et al., 2010 Krönke et al., 2014 Lu et al., 2014). For example, macrocyclic natural products cyclosporin A, FK506, and rapamycin recruit FKBP proteins to the phosphatase calcineurin or the kinase mTORC1, interfering with their enzymatic activities to control intracellular signal transduction ( Brown et al., 1994 Liu et al., 1991 Sabatini et al., 1994). Notwithstanding, molecular glues are rare and were discovered serendipitously only a handful of molecular glues have been documented over the past four decades. As a result, molecular glues have been viewed enthusiastically as a unique pharmacological modality to target proteins without druggable pockets ( Maniaci and Ciulli, 2019). Unlike conventional small molecules that bind to active sites or allosteric sites to modulate the activity of their target proteins, molecular glues influence the activity or fate of their target proteins by bringing them to the vicinity of regulatory proteins. The name ‘molecular glue’ was first coined to describe the mechanism of action of the plant hormone auxin, which bridges an interaction between the E3 ubiquitin ligase TIR1 and IAA transcription repressors, leading to IAA destruction by the ubiquitin-proteasome system to activate auxin-response gene expression ( Tan et al., 2007). Molecular glues are a class of small molecules that induce the formation of protein-protein interactions to elicit biologic or therapeutic effects. Our studies reveal a new molecular glue that recruits its target protein directly to DDB1 to bypass the requirement of a substrate-specific receptor, presenting a new strategy for targeted protein degradation. Structure-activity relationship analysis of HQ461 revealed the importance of a 5-methylthiazol-2-amine pharmacophore and resulted in an HQ461 derivate with improved potency. Degradation of CCNK mediated by HQ461 compromised CDK12 function, leading to reduced phosphorylation of a CDK12 substrate, downregulation of DNA damage response genes, and cell death. Using loss-of-function and gain-of-function genetic screening in human cancer cells followed by biochemical reconstitution, we show that HQ461 acts by promoting an interaction between CDK12 and DDB1-CUL4-RBX1 E3 ubiquitin ligase, leading to polyubiquitination and degradation of CDK12-interacting protein Cyclin K (CCNK). Here, we report a new molecular glue HQ461 discovered by high-throughput screening. Molecular-glue degraders mediate interactions between target proteins and components of the ubiquitin-proteasome system to cause selective protein degradation.
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