Degradation of CCNK/CDK12 is a druggable vulnerability of colorectal cancer

Dieter, Sebastian M.; Siegl, Christine; Codó, Paula; Huerta, Mario; Ostermann-Parucha, Anna L.; Schulz, E; Zowada, Martina K.; Martin, Sylvia; Laaber, Karin; Nowrouzi, Ali; Blatter, Mona; Kreth, Sina; Westermann, Frank; Benner, Axel; Uhrig, Ulrike; Putzker, Kerstin; Lewis, Joe; Haegebarth, Andrea; Mumberg, Dominik; Holton, Simon J.; Weiske, Joerg; Toepper, Lena-Marit; Scheib, U.; Siemeister, Gerhard; Ball, Claudia R.; Küster, Bernhard; Stoehr, Gabriele; Hahne, Hannes; Johannes, Sarah; Lange, Martin; Herbst, Friederike; Glimm, Hanno

doi:10.1016/j.celrep.2021.109394

Cited by 51 publications

(40 citation statements)

References 61 publications

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“…Examples here include the approved IMiD class, which relies on CRBN to degrade IKZF1/IKZF3 (refs 4 , 5 ) via a molecular glue mechanism; sulfonamides previously in clinical trials 81 , 82 that have since been shown to use DCAF15 to degrade RBM39 (refs 25 , 27 , 29 ), also via a molecular glue mechanism elucidated by elegant structural biology in recent work by multiple groups 26 , 28 , 83 ; and, most recently, a unique class of cyclin-dependent kinase 12 (CDK12) inhibitors, exemplified by CR8, which, unexpectedly, has been shown to directly co-opt DDB1 as an E3 ligase for the degradation of cyclin K (CCNK) 84 – 86 . In fact, not only CR8, but four separate classes of compounds, each discovered by a different screening method, were found to have molecular glue-like properties in potentiating the interaction of DDB1 and CDK12, resulting in CCNK degradation 84 – 87 . These findings suggest that many more compounds, including those approved or already in the clinic, could have a hitherto overlooked degrader contribution to their mechanism of action.…”

Section: Outlook For the Next 20 Years Of Tpdmentioning

confidence: 99%

PROTAC targeted protein degraders: the past is prologue

Békés

Langley

Crews

2022

Nat Rev Drug Discov

1,290

996

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Targeted protein degradation (TPD) is an emerging therapeutic modality with the potential to tackle disease-causing proteins that have historically been highly challenging to target with conventional small molecules. In the 20 years since the concept of a proteolysis-targeting chimera (PROTAC) molecule harnessing the ubiquitin–proteasome system to degrade a target protein was reported, TPD has moved from academia to industry, where numerous companies have disclosed programmes in preclinical and early clinical development. With clinical proof-of-concept for PROTAC molecules against two well-established cancer targets provided in 2020, the field is poised to pursue targets that were previously considered ‘undruggable’. In this Review, we summarize the first two decades of PROTAC discovery and assess the current landscape, with a focus on industry activity. We then discuss key areas for the future of TPD, including establishing the target classes for which TPD is most suitable, expanding the use of ubiquitin ligases to enable precision medicine and extending the modality beyond oncology.

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Section: Outlook For the Next 20 Years Of Tpdmentioning

confidence: 99%

PROTAC targeted protein degraders: the past is prologue

Békés

Langley

Crews

2022

Nat Rev Drug Discov

1,290

996

View full text Add to dashboard Cite

show abstract

“…Interestingly, by screening a small-molecule library against primary colorectal cancer (CRC) heterogeneous spheroids, Dieter et al found a compound named NCT02 with a chemical structure similar to HQ461 ( Figure 4 A) that acts as an MG degrader to induce ubiquitination of cyclin K (CCNK) and proteasomal degradation of both CCNK and its partner CDK12 [ 28 ].…”

Section: Molecular Glues For Cancer Treatmentmentioning

confidence: 99%

Molecular Glues: Capable Protein-Binding Small Molecules That Can Change Protein–Protein Interactions and Interactomes for the Potential Treatment of Human Cancer and Neurodegenerative Diseases

Aljahdali

Ling

2022

IJMS

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Molecular glue (MG) compounds are a type of unique small molecule that can change the protein–protein interactions (PPIs) and interactomes by degrading, stabilizing, or activating the target protein after their binging. These small-molecule MGs are gradually being recognized for their potential application in treating human diseases, including cancer. Evidence suggests that small-molecule MG compounds could essentially target any proteins, which play critical roles in human disease etiology, where many of these protein targets were previously considered undruggable. Intriguingly, most MG compounds with high efficacy for cancer treatment can glue on and control multiple key protein targets. On the other hand, a single key protein target can also be glued by multiple MG compounds with distinct chemical structures. The high flexibility of MG–protein interaction profiles provides rich soil for the growth and development of small-molecule MG compounds that can be used as molecular tools to assist in unraveling disease mechanisms, and they can also facilitate drug development for the treatment of human disease, especially human cancer. In this review, we elucidate this concept by using various types of small-molecule MG compounds and their corresponding protein targets that have been documented in the literature.

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“…After 2 h incubation, fluorescence intensity was measured using a Tecan reader. Alternatively, the ATP lite luminescence assay (Perkin Elmer, Waltham, MA, United States) was used as described before [ 61 ]. For combination treatment of Afatinib (MedChemExpress, Monmouth Junction, NJ, United States) with Vemurafenib, a fixed Vemurafenib dose was used and 20-point dilutions of Afatinib (50 µM to 95 pM) were performed as indicated in the respective figure legends.…”

Section: Methodsmentioning

confidence: 99%

Suppression of heparan sulfation re-sensitizes YAP1-driven melanoma to MAPK pathway inhibitors

et al. 2022

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Accumulating evidence identifies non-genetic mechanisms substantially contributing to drug resistance in cancer patients. Preclinical and clinical data implicate the transcriptional co-activators YAP1 and its paralog TAZ in resistance to multiple targeted therapies, highlighting the strong need for therapeutic strategies overcoming YAP1/TAZ-mediated resistance across tumor entities. Here, we show particularly high YAP1/TAZ activity in MITFlow/AXLhigh melanomas characterized by resistance to MAPK pathway inhibition and broad receptor tyrosine kinase activity. To uncover genetic dependencies of melanoma cells with high YAP1/TAZ activity, we used a genome-wide CRISPR/Cas9 functional screen and identified SLC35B2, the 3′-phosphoadenosine-5′-phosphosulfate transporter of the Golgi apparatus, as an essential gene for YAP1/TAZ-driven drug resistance. SLC35B2 expression correlates with tumor progression, and its loss decreases heparan sulfate expression, reduces receptor tyrosine kinase activity, and sensitizes resistant melanoma cells to BRAF inhibition in vitro and in vivo. Thus, targeting heparan sulfation via SLC35B2 represents a novel approach for breaking receptor tyrosine kinase-mediated resistance to MAPK pathway inhibitors.

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Degradation of CCNK/CDK12 is a druggable vulnerability of colorectal cancer

Cited by 51 publications

References 61 publications

PROTAC targeted protein degraders: the past is prologue

PROTAC targeted protein degraders: the past is prologue

Molecular Glues: Capable Protein-Binding Small Molecules That Can Change Protein–Protein Interactions and Interactomes for the Potential Treatment of Human Cancer and Neurodegenerative Diseases

Suppression of heparan sulfation re-sensitizes YAP1-driven melanoma to MAPK pathway inhibitors

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