Degradation of CCNK/CDK12 is a druggable vulnerability of colorectal cancer
- By Cytoskeleton Inc. - Signal-Seeker News
- Jun 23, 2022
Novel therapies are needed to combat cancer cells that acquire resistance to current treatments, as well as, to find more efficacious drugs with defined mechanisms and better therapeutic windows. Dieter et al. sought to identify a novel treatment for colorectal cancer (CRC); utilizing an array of techniques and validation models they identified NCT02 as a novel therapeutic that specifically treated a subset of CRCs. To achieve their goal, an 80,000 small molecule library screen was tested against patient-derived CRC spheroids. After multiple rounds of validation and selective screening, 14 compounds were chosen for additional testing. These compounds were analyzed against eight different tumor spheroid cultures as well as primary fibroblasts, the result was NCT02 being identified as a suitable drug that targeted a subset of CRCs while lacking activity against primary fibroblasts. The group then utilized transcriptome analysis tools to identify the molecular pathways regulated by NCT02, which revealed several converging DNA damaging pathways as targets of this drug. This data was complemented with proteomic studies and together helped identify cyclin k (CCNK) and cyclin dependent kinase 12 (CDK12) as potential targets. Molecular studies showed that NCT02 triggers degradation of the CCNK/CDK12 complex via the proteasome. Interestingly, NCT02 interacts with CDK12 while inducing ubiquitination of CCNK in a DDB1 dependent manner, in essence it is acting as a molecular glue degrader. Additional structural studies were utilized to further define this complex interaction. Ultimately, knockout of CCNK and/or CDK12 showed that NCT02 targets this protein complex to selectively suppress cancer cell progression in vitro and in patient-derived xenografts. Cytoskeleton’s ubiquitin affinity beads (Cat. # UBA01-beads) was an essential tool to define NCT02’s ability to promote ubiquitination of CCNK but not CDK12. It will be of great interest to see how drugs that act as molecular glue degraders perform as viable cancer therapeutics.
Schematic of NCT02 targeting CCNK for ubiquitination
Link to Citation:
Dieter S. et al. Degradation of CCNK/CDK12 is a druggable vulnerability of colorectal cancer. Cell Rep. 2021 Jul 20;36(3):109394. doi: 10.1016/j.celrep.2021.109394.
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