Céline Moison, Rodrigo Mendoza-Sanchez, Deanne Gracias, Doris A Schuetz, Jean-François Spinella, Simon Girard, Bounkham Thavonekham, Jalila Chagraoui, Aurélie Durand, Simon Fortier, Tara MacRae, Eric Bonneil, Yannick Rose, Nadine Mayotte, Isabel Boivin, Pierre Thibault, Josée Hébert, Réjean Ruel, Anne Marinier, Guy Sauvageau
{"title":"DDB1的结合定义了S656类似物对细胞周期蛋白K降解的选择性，而不是CDK抑制。","authors":"Céline Moison, Rodrigo Mendoza-Sanchez, Deanne Gracias, Doris A Schuetz, Jean-François Spinella, Simon Girard, Bounkham Thavonekham, Jalila Chagraoui, Aurélie Durand, Simon Fortier, Tara MacRae, Eric Bonneil, Yannick Rose, Nadine Mayotte, Isabel Boivin, Pierre Thibault, Josée Hébert, Réjean Ruel, Anne Marinier, Guy Sauvageau","doi":"10.1038/s44319-025-00448-y","DOIUrl":null,"url":null,"abstract":"<p><p>In efforts to identify additional therapeutic targets for Acute Myeloid Leukemia (AML), we performed a high-throughput screen that includes 56 primary specimens tested with 10,000 structurally diverse small molecules. One specific hit, called S656 acts as a molecular glue degrader (MGD), that mediates the CRL4-dependent proteolysis of cyclin K. Structurally, S656 features a moiety that binds to the ATP binding site of cyclin-dependent kinases (CDKs), allowing the recruitment of the CDK12-cyclin K complex, along with a binding site for DDB1 bridging the CRL4 complex. Structure activity relationship studies reveal that minimal modifications to the dimethylaniline moiety of S656 improve its cyclin K MGD function over CDK inhibition by promoting DDB1 engagement. This includes full occupation of the DDB1 pocket, preferably with hydrophobic terminal groups, and cation-π interaction with Arg928. Additionally, we demonstrate that despite structural diversity, cyclin K degraders exhibit similar functional activity in AML which is distinct from direct CDK12 inhibition.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5000,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"DDB1 engagement defines the selectivity of S656 analogs for cyclin K degradation over CDK inhibition.\",\"authors\":\"Céline Moison, Rodrigo Mendoza-Sanchez, Deanne Gracias, Doris A Schuetz, Jean-François Spinella, Simon Girard, Bounkham Thavonekham, Jalila Chagraoui, Aurélie Durand, Simon Fortier, Tara MacRae, Eric Bonneil, Yannick Rose, Nadine Mayotte, Isabel Boivin, Pierre Thibault, Josée Hébert, Réjean Ruel, Anne Marinier, Guy Sauvageau\",\"doi\":\"10.1038/s44319-025-00448-y\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>In efforts to identify additional therapeutic targets for Acute Myeloid Leukemia (AML), we performed a high-throughput screen that includes 56 primary specimens tested with 10,000 structurally diverse small molecules. One specific hit, called S656 acts as a molecular glue degrader (MGD), that mediates the CRL4-dependent proteolysis of cyclin K. Structurally, S656 features a moiety that binds to the ATP binding site of cyclin-dependent kinases (CDKs), allowing the recruitment of the CDK12-cyclin K complex, along with a binding site for DDB1 bridging the CRL4 complex. Structure activity relationship studies reveal that minimal modifications to the dimethylaniline moiety of S656 improve its cyclin K MGD function over CDK inhibition by promoting DDB1 engagement. This includes full occupation of the DDB1 pocket, preferably with hydrophobic terminal groups, and cation-π interaction with Arg928. Additionally, we demonstrate that despite structural diversity, cyclin K degraders exhibit similar functional activity in AML which is distinct from direct CDK12 inhibition.</p>\",\"PeriodicalId\":11541,\"journal\":{\"name\":\"EMBO Reports\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":6.5000,\"publicationDate\":\"2025-04-28\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"EMBO Reports\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1038/s44319-025-00448-y\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"EMBO Reports","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1038/s44319-025-00448-y","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
DDB1 engagement defines the selectivity of S656 analogs for cyclin K degradation over CDK inhibition.
In efforts to identify additional therapeutic targets for Acute Myeloid Leukemia (AML), we performed a high-throughput screen that includes 56 primary specimens tested with 10,000 structurally diverse small molecules. One specific hit, called S656 acts as a molecular glue degrader (MGD), that mediates the CRL4-dependent proteolysis of cyclin K. Structurally, S656 features a moiety that binds to the ATP binding site of cyclin-dependent kinases (CDKs), allowing the recruitment of the CDK12-cyclin K complex, along with a binding site for DDB1 bridging the CRL4 complex. Structure activity relationship studies reveal that minimal modifications to the dimethylaniline moiety of S656 improve its cyclin K MGD function over CDK inhibition by promoting DDB1 engagement. This includes full occupation of the DDB1 pocket, preferably with hydrophobic terminal groups, and cation-π interaction with Arg928. Additionally, we demonstrate that despite structural diversity, cyclin K degraders exhibit similar functional activity in AML which is distinct from direct CDK12 inhibition.
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EMBO Reports is a scientific journal that specializes in publishing research articles in the fields of molecular biology, cell biology, and developmental biology. The journal is known for its commitment to publishing high-quality, impactful research that provides novel physiological and functional insights. These insights are expected to be supported by robust evidence, with independent lines of inquiry validating the findings.
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