Development of selective mono or dual PROTAC degrader probe of CDK isoforms

CDK Family PROTAC Profiling Reveals Distinct Kinetic Responses and Cell Cycle–Dependent Degradation of CDK2

“…However, the ability to develop CDK-specific degraders has been demonstrated, indicating that selectivity within the family is achievable. 19,[21][22][23][24] In addition, in an exciting recent development involving CDKs, it was demonstrated that a CDK inhibitor could function as a molecular glue degrader, bringing together the CDK12-cyclin K complex with DDB1, a component of the E3 CUL4 ring ligase (CRL4) complex, which then promoted the ubiquitination and degradation of cyclin K. 32 CDK degradation has also been observed in key landmark studies of pan-kinase inhibitors converted to PROTAC compounds. 20,25 These data from independent groups revealed pan-kinase PROTACs selectively degraded only a small fraction of their kinases targets, despite being able to bind nearly all with similar affinity as the promiscuous parental inhibitors.…”

“…[7][8][9][10][11][12][13][14][15] Indeed, initial comparison of kinase inhibitors with degraders supported this hypothesis, [16][17][18][19] and many following studies have shown that kinases in general, including single-pass transmembrane receptor tyrosine kinases, are readily amenable for degradation using heterobifunctional proteolysis-targeted chimera (PROTAC) compounds. [16][17][18][19][20][21][22][23][24][25] One of the major families within the kinome found to be degraded well with PROTAC compounds was that of the serine-threonine cyclin-dependent kinases (CDKs), [19][20][21][22][23][24][25] which are key therapeutic targets for cancer and inflammation. 1,4,[26][27][28][29][30][31] CDKs regulate cell-signaling pathways, transcription, and transition through cell cycle and cell division.…”

“…1,4,[26][27][28][29][30][31] CDKs regulate cell-signaling pathways, transcription, and transition through cell cycle and cell division. 1,14,23,24,[29][30][31] There are 21 family members of the CDK family, although only those involved in cell cycle (CDK1, 2, 4, and 6) and transcriptional regulation (CDK7, 8, 9, 12, and 13) are currently well characterized or understood. 1,4,[26][27][28][29][30][31] Even for well-studied CDKs, regulation of activity has shown to be highly complex and is governed by a diverse set of factors, including tightly controlled autoregulatory expression of expression or their binding partners, differential pairing combinations with cyclins or cyclin-like regulatory proteins, interactions with CDK interacting protein/kinase inhibitory proteins (CIP/ KIPs), and posttranslational modifications such as phosphorylation or ubiquitination.…”

“…7–15 Indeed, initial comparison of kinase inhibitors with degraders supported this hypothesis, 16–19 and many following studies have shown that kinases in general, including single-pass transmembrane receptor tyrosine kinases, are readily amenable for degradation using heterobifunctional proteolysis-targeted chimera (PROTAC) compounds. 16–25…”

“…One of the major families within the kinome found to be degraded well with PROTAC compounds was that of the serine-threonine cyclin-dependent kinases (CDKs), 19–25 which are key therapeutic targets for cancer and inflammation. 1,4,26–31 CDKs regulate cell-signaling pathways, transcription, and transition through cell cycle and cell division.…”