Author: Cigler, Marko ; Schmid-Burgk, Jonathan L ; Suchyta, Dakota J ; Gillingham, Dennis ; Fischer, Eric S ; Thomä, Nicolas H ; Słabicki, Mikołaj ; Petzold, Georg ; Häussinger, Daniel ; Zou, Charles ; Kempf, Georg ; Mayor-Ruiz, Cristina ; Ebert, Benjamin L ; Jentzsch, Marius ; Winter, Georg E ; Coomar, Seemon ; Kozicka, Zuzanna ; Donovan, Katherine A ; Di Genua, Cristina ; Focht, Vivian

AbstractMolecular glue degraders are an effective therapeutic modality, but their design principles are not well understood. Recently, several unexpectedly diverse compounds were reported to deplete cyclin K by linking CDK12–cyclin K to the DDB1–CUL4–RBX1 E3 ligase. Here, to investigate how chemically dissimilar small molecules trigger cyclin K degradation, we evaluated 91 candidate degraders in structural, biophysical and cellular studies and reveal all compounds acquire glue activity via simultaneous CDK12 binding and engagement of DDB1 interfacial residues, in particular Arg928. While we identify multiple published kinase inhibitors as cryptic degraders, we also show that these glues do not require pronounced inhibitory properties for activity and that the relative degree of CDK12 inhibition versus cyclin K degradation is tuneable. We further demonstrate cyclin K degraders have transcriptional signatures distinct from CDK12 inhibitors, thereby offering unique therapeutic opportunities. The systematic structure–activity relationship analysis presented herein provides a conceptual framework for rational molecular glue design.

14 Jul 2022·Journal of Medicinal ChemistryQ1 · MEDICINE

3,5,7-Substituted Pyrazolo[4,3-d]Pyrimidine Inhibitors of Cyclin-Dependent Kinases and Cyclin K Degraders

Q1 · MEDICINE

Article

Author: Renešová, Nicol ; Jorda, Radek ; Klener, Pavel ; Vojáčková, Veronika ; Djukic, Stefan ; Havlíček, Libor ; Peřina, Miroslav ; Kryštof, Vladimír ; Škerlová, Jana ; Strnad, Miroslav ; Řezáčová, Pavlína ; Pospíšil, Tomáš ; Grúz, Jiří

3,5,7-Trisubstituted pyrazolo[4,3-d]pyrimidines have been identified as potent inhibitors of cyclin-dependent kinases (CDKs), which are established drug targets. Herein, we describe their further structural modifications leading to novel nanomolar inhibitors with strong antiproliferative activity. We determined the crystal structure of fully active CDK2/A2 with 5-(2-amino-1-ethyl)thio-3-cyclobutyl-7-[4-(pyrazol-1-yl)benzyl]amino-1(2)H-pyrazolo[4,3-d]pyrimidine (24) at 1.7 Å resolution, confirming the competitive mode of inhibition. Biochemical and cellular assays in lymphoma cell lines confirmed the expected mechanism of action through dephosphorylation of retinoblastoma protein and RNA polymerase II, leading to induction of apoptosis. Importantly, we also revealed an interesting ability of compound 24 to induce proteasome-dependent degradation of cyclin K both in vitro and in a patient-derived xenograft in vivo. We propose that 24 has a dual mechanism of action, acting as a kinase inhibitor and as a molecular glue inducing an interaction between CDK12 and DDB1 that leads to polyubiquitination of cyclin K and its subsequent degradation.

01 Nov 2020·Nature Chemical Biology

Prospecting for molecular glues

Article

Author: den Besten, Willem ; Lipford, J Russell

A review with commentary on the research of Slabicki et al. (Nature https://doi.org/10.1038/s41586-020-2374-x (2020)) and Mayor-Ruiz et al. (Nat. Chem. Biol. https://doi.org/10.1038/s41589-020-0594-x (2020)).Two recent studies identified CDK12 inhibitors that bind to CDK12-cyclin K complexes and act as mol. glues to stabilize an interaction with the ubiquitin ligase CUL4-DDB1, leading to cyclin K degradation

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