CDK6 inhibitors bind CDK6

Stable Identifier
R-HSA-9754129
Type
Reaction [transition]
Species
Homo sapiens
Compartment
ReviewStatus
5/5
Locations in the PathwayBrowser
General
SVG |   | PPTX  | SBGN
Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout
The following small kinase inhibitors have been shown to compete with ATP binding and inhibit the catalytic activity of CDK6 in the context of the CDK6 complex with cyclin D1 (CCND1):

Abemaciclib (LY2835219): inhibits CDK6:CCND1-mediated phosphorylation of RB1 at residue S780 (Gelbert et al. 2014) and at S807 and S811 (Chen et al. 2016);

Dinaciclib (SHC727965): inhibits CDK6-mediated phosphorylation of RB1 on residues S807 and S811 (Chen et al. 2016);

Fascaplysin: inhibits phosphorylation of RB1 at residues S780 and S795 (Soni et al. 2000); it is 10 times less effective against CDK6:CCND1 than CDK4:CCND1; shows negligible activity against the complex of CDK6 and cyclin D2 (CCND2);

Palbociclib (PD-0332991): inhibits CDK6-mediated phosphorylation of RB1 on residues S807 and S811 (Chen et al. 2016);

Ribociclib: inhibits CDK6-mediated phosphorylation of RB1 on residues S807 and S811, but is less potent than palbociclib (Chen et al. 2016);

Voruciclib (P1446A): ~5 times less potent against the complex of CDK6 and CCND1 (~3 nM) than against CDK9 (~0.7 nM) (Dey et al. 2017); inhibits phosphorylation of RB1 on residues S780 and T821 (Paiva et al. 2015);

Dalpiciclib (SHR6390): annotated as a candidate CDK6 inhibitor; binding to and inhibition of CDK6 have not been tested outside the patent registration (patent number WO2014183520A1); inhibits RB1 phosphorylation at residue S780 (Wang, Li et al. 2017, Long et al. 2019);

PF-06873600 (ebvaciclib): annotated as a candidate CDK6 inhibitor; competes with ATP for binding to activated CDK6 (tested using CDK6 complex with CCND1), primarily targeting CDK2 and showing higher efficacy against CDK6 than CDK4; inhibition of RB1 phosphorylation observed but publication pending (Freeman-Cook et al. 2021).


The following small kinase inhibitors are annotated as inhibitors of the CDK6 in complex with cyclin D2 (CCND2):

Palbociclib: inhibits the complex of CDK6 and CCND2 (Fry et al. 2004) and phosphorylation of RB1 on residues S780 and S795 (Fry et al. 2004); leads to G1 arrest in CCND2 expressing cells (Smith et al. 2016, Nakatani et al. 2021);

Abemaciclib: annotated as a candidate; inhibits proliferation of acute myeloid leukemia (AML) cells expressing high levels of CCND2 (Nakatani et al. 2021);

Dalpiciclib (SHR6390): annotated as a candidate CDK6 inhibitor; binding to and inhibition of CDK6 have not been tested outside the patent registration (patent number WO2014183520A1); inhibits RB1 phosphorylation at residue S780 (Wang, Li et al. 2017, Long et al. 2019);


The following small kinase inhibitors have been shown to compete with ATP binding and inhibit the catalytic activity of CDK6 in the context of the CDK6 complex with cyclin D3 (CCND3):

Lerociclib (G1T38): inhibits phosphorylation of RB1 at residues S807 amd S811 (Bisi et al. 2017);

Trilaciclib (G1T28): inhibits phosphorylation of RB1 at residues S807 amd S811 (Bisi et al. 2016);

Dalpiciclib (SHR6390): annotated as a candidate CDK6 inhibitor; binding to and inhibition of CDK6 have not been tested outside the patent registration (patent number WO2014183520A1); inhibits RB1 phosphorylation at residue S780 (Wang, Li et al. 2017, Long et al. 2019);

Palbociclib (PD-0332991): annotated as a candidate; inhibits CDK6-mediated phosphorylation of RB1 but the effect may depend on the association of the CDK6:CCND3 dimer with p21 and p27;

Ribociclib: annotated as a candidate; especially effective in inhibiting growth of tumors expressing high levels of CDK6 and CCND3 (Wang, Nicolay et al. 2017);

Riviciclib (P276-00): annotated as a candidate CDK6 inhibitor; it was shown to competes with ATP for binding to activated CDK6, tested using the complex of CDK6 and CCND3, but is ~6 times less efficient in inhibiting CDK6 (~400 nM) than CDK4 (~60 nM) (Joshi et al. 2007).
Literature References
PubMed ID Title Journal Year
34110834 Discovery of PF-06873600, a CDK2/4/6 Inhibitor for the Treatment of Cancer

Visswanathan, R, Hoffman, RL, O'Doherty, I, Kephart, SE, Miller, N, Huser, N, Carelli, J, Tseng, E, Nagata, A, Murray, BW, Behenna, DC, Freeman-Cook, KD, Hui, A, Ninkovic, S, Lapek, J, Nguyen, L, Ornelas, MA, Huang, B, Sutton, SC, Jones, R, Zehnder, L, Tran, K, Boras, B, Dann, S, Zhang, C, He, YA, Ferre, RA, Solowiej, J, Xu, M, Zhang, Q, Diehl, W, McTigue, M, Niessen, S

J Med Chem 2021
10973815 Inhibition of cyclin-dependent kinase 4 (Cdk4) by fascaplysin, a marine natural product

Muller, L, Stephan, C, Furet, P, Fretz, H, Zumstein-Mecker, S, Schoepfer, J, Soni, R, Chaudhuri, B

Biochem Biophys Res Commun 2000
15542782 Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts

Fry, DW, Meade, M, Keller, PR, Trachet, E, Toogood, PL, Leopold, WR, Pryer, NK, Albassam, M, Harvey, PJ, Elliott, WL, Zheng, X

Mol Cancer Ther 2004
30724426 Preclinical characterization of SHR6390, a novel CDK 4/6 inhibitor, in vitro and in human tumor xenograft models

Fu, H, Li, Y, Wang, Y, Lou, L, Wang, Q, Xie, C, Long, F, Bao, X, He, Y

Cancer Sci 2019
25486476 The CDK4/CDK6 inhibitor PD0332991 paradoxically stabilizes activated cyclin D3-CDK4/6 complexes

Bisteau, X, Paternot, S, Colleoni, B, Roger, PP

Cell Cycle 2014
26826116 Preclinical Characterization of G1T28: A Novel CDK4/6 Inhibitor for Reduction of Chemotherapy-Induced Myelosuppression

Tavares, FX, Strum, JC, Roberts, PJ, Bisi, JE, Sorrentino, JA

Mol Cancer Ther 2016
17363486 In vitro antitumor properties of a novel cyclin-dependent kinase inhibitor, P276-00

Sivakumar, M, Sharma, S, Joshi, KS, Lal, B, Rathos, MJ, Joshi, RD, Kamble, S, Mascarenhas, M

Mol Cancer Ther 2007
27146121 Cyclin D type does not influence cell cycle response to DNA damage caused by ionizing radiation in multiple myeloma tumours

Smith, D, Mann, D, Yong, K

Br J Haematol 2016
26606677 Cyclin-Dependent Kinase Inhibitor P1446A Induces Apoptosis in a JNK/p38 MAPK-Dependent Manner in Chronic Lymphocytic Leukemia B-Cells

Brown, JR, Kilmarx, S, Spurgeon, SE, Paiva, C, Srinivasa, SP, Soderquist, RS, Danilov, AV, Rowland, T, Godbersen, JC

PLoS One 2015
28578693 CDK4/6 inhibitor-SHR6390 exerts potent antitumor activity in esophageal squamous cell carcinoma by inhibiting phosphorylated Rb and inducing G1 cell cycle arrest

Li, Z, Yuan, J, Wang, J, Li, Q, Liu, Z, Chen, Z, Shen, L, Gao, J, Lai, Y, Wang, J

J Transl Med 2017
27496135 Spectrum and Degree of CDK Drug Interactions Predicts Clinical Performance

Bergqvist, S, He, YA, Lam, H, Nagata, A, Lee, NV, Hu, W, Chen, P, Murray, BW, Ferre, RA, VanArsdale, T, Solowiej, J, Xu, M, Yu, X, Diehl, W

Mol Cancer Ther 2016
28418845 Preclinical development of G1T38: A novel, potent and selective inhibitor of cyclin dependent kinases 4/6 for use as an oral antineoplastic in patients with CDK4/6 sensitive tumors

Tavares, FX, Jordan, JL, Darr, DD, Strum, JC, Roberts, PJ, Bisi, JE, Sorrentino, JA

Oncotarget 2017
29269870 Voruciclib, a clinical stage oral CDK9 inhibitor, represses MCL-1 and sensitizes high-risk Diffuse Large B-cell Lymphoma to BCL2 inhibition

Gillespie, KC, Merrell, AJ, Burns, C, Kerwin, WS, Deckwerth, TL, Dixon, CP, Dey, J, Casalini, JR, Grenley, MO, Klinghoffer, RA, Ditzler, SH, Beirne, E, Kleinman, EF

Sci Rep 2017
28607489 The metabolic function of cyclin D3-CDK6 kinase in cancer cell survival

Roberts, TM, Gygi, SP, Geng, Y, Polyak, K, Sicinska, E, Sicinski, P, Gao, X, Williams, JA, Wang, H, Yang, G, Gerdemann, U, Keibler, MA, Suski, JM, Ren, H, Chick, JM, Dyson, NJ, Haining, WN, Nicolay, BN, Gao, H

Nature 2017
33068248 Inhibition of CDK4/6 and autophagy synergistically induces apoptosis in t(8;21) acute myeloid leukemia cells

Nishinaka-Arai, Y, Nakatani, K, Koyama, A, Noura, M, Adachi, S, Kamikubo, Y, Harata, Y, Higashitani, M, Matsuo, H

Int J Hematol 2021
24919854 Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine

Flack, RS, Sanchez-Martinez, C, Del Prado, M, Neubauer, BL, Lallena, MJ, Gelbert, LM, Chan, EM, Iversen, P, Lin, X, Torres, R, Ajamie, RT, de Dios, A, Kreklau, E, Cai, S, Cronier, D, Young, J, Wishart, GN

Invest New Drugs 2014
Participants
Participates
Orthologous Events
Authored
Reviewed
Created
Cite Us!