CDK4 inhibitors bind CDK4

Stable Identifier
R-HSA-9754130
Type
Reaction [transition]
Species
Homo sapiens
Compartment
nucleoplasm
ReviewStatus
5/5
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CDK4 inhibitors bind CDK4
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The following small kinase inhibitors have been shown to compete with ATP binding and inhibit the catalytic activity of CDK4 in the context of the CDK4 complex with cyclin D1 (CCND1):

Abemaciclib (LY2835219): inhibits phosphorylation of RB1 at residue S780 by the complex of CDK4 and CCND1 (Gelbert et al. 2014);

Alvocidib (flavopiridol): inhibits CDK4-mediated phosphorylation of RB1 (Carlson et al. 1996);

Fascaplysin: inhibits phosphorylation of RB1 at residues S780 and S795 (Soni et al. 2000); shows negligible activity against the complex of CDK4 and cyclin D2 (CCND2), and the complex of CDK4 and cyclin D3 (CCND3);

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

Palbociclib (PD-0332991): binds to the dimers of CDK4 and CCND1 and inhibits CDK4:CCND1-mediated phosphorylation of RB1 (Fry et al. 2004; Guiley et al. 2019) on residues S780 and S795 (Fry et al. 2004); ineffective against trimers of CDK4, CCND1 and p27 (Guiley et al. 2019);

R547: inhibits phosphorylation of RB1 at residues S780 and S795 (DePinto et al. 2006);

RGB-286638: inhibits phosphorylation of RB1 at residues S807 and S811, to a lesser extent at S780 (Cirstea et al. 2013);

Ribociclib: inhibits CDK4:CCND1-mediated phosphorylation of RB1; ineffective against trimers of CDK4, CCND1 and p27 (Guiley et al. 2019);

Riviciclib (P276-00): inhibits CDK4-mediated phosphorylation of RB1 on residue S780 (Joshi et al. 2007);

RO-0505124: inhibits CDK4-mediated phosphorylation of RB1 at residue S795 (Burgess et al. 2006);

RO-0506220: inhibits CDK4-mediated phosphorylation at residue S795 (Burgess et al. 2006);

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

Voruciclib (P1446A): ~5 times less potent against the complex of CDK4 and CCND1 (~4 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 CDK4 inhibitor; binding to and inhibition of CDK4 have not been tested outside the patent registration (patent number WO2014183520A1); inhibits RB1 phosphorylation at residue S780 (Wang et al. 2017, Long et al. 2019);

K00024 (indolocarbazole derivative 4d): annotated as a candidate CDK4 inhibitor; competes with ATP for binding to activated CDK4 (tested using CDK4 complex with CCND1 - species from which the CDK4:CCND1 complex was derived was not specified in the study); the effect on RB1 phosphorylation has not been tested (Zhu et al. 2003);

Milciclib (PHA848125): annotated as a candidate CDK4 inhibitor; moderately inhibits the complex of CDK4 and CCND1; the effect on RB1 phosphorylation has not been tested (Jorda et al. 2018);

PF-06873600 (ebvaciclib): annotated as a candidate CDK4 inhibitor; competes with ATP for binding to activated CDK4 (tested using CDK4 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 candidate inhibitors of the CDK4 in complex with cyclin D2 (CCND2):

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 CDK4 inhibitor; binding to and inhibition of CDK4 have not been tested outside the patent registration (patent numberWO2014183520A1); inhibits RB1 phosphorylation at residue S780 (Wang et al. 2017, Long et al. 2019);

Palbociclib (PD-0332991): annotated as a candidate; leads to G1 arrest in CCND2 expressing cells (Smith et al. 2016, Nakatani et al. 2021).


The following small kinase inhibitors have been shown to compete with ATP binding and inhibit the catalytic activity of CDK4 in the context of the CDK4 complex with cyclin D3 (CCND3):

Abemaciclib (LY2835219): also shown to inhibit RB1 phosphorylation at S807 and S811 (Chen et al. 2016);

Dinaciclib (SHC727965): inhibits CDK4-mediated phosphorylation of RB1 on residues S807 and S811 (Chen et al. 2016);

Palbociclib (PD-0332991): inhibits the complex of CDK4 and CCND3 (Fry et al. 2004; Chen et al. 2016); inhibits CDK4-mediated phosphorylation of RB1 on residues S780 and S795 (Fry et al. 2004), as well as S807 and S811 (Chen et al. 2016); the effect may depend on the association of the CDK4:CCND3 dimer with p21 and p27, so that palbociclib is effective against the trimers of CDK4, CCND3 and p21/p27, and ineffective against CDK4:CCND3 dimers (Paternot et al. 2014);

Ribociclib (LE-0011): inhibits CDK4-mediated phosphorylation of RB1 on residues S807 and S811, but is less potent than palbociclib (Chen et al. 2016);

Dalpiciclib (SHR6390): annotated as a candidate CDK4 inhibitor; binding to and inhibition of CDK4 have not been tested outside the patent registration (patent number WO2014183520A1); inhibits RB1 phosphorylation at residue S780 (Wang et al. 2017, Long et al. 2019).
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
23807770 Small-molecule multi-targeted kinase inhibitor RGB-286638 triggers P53-dependent and -independent anti-multiple myeloma activity through inhibition of transcriptional CDKs

Hideshima, T, Anderson, KC, Ohguchi, H, Suzuki, R, Mishima, Y, Santo, L, Nemani, N, Raje, N, Hu, Y, Mimura, N, Gorgun, G, Cottini, F, Eda, H, Loferer, H, Munshi, NC, Cirstea, D

Leukemia 2013
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
30234987 How Selective Are Pharmacological Inhibitors of Cell-Cycle-Regulating Cyclin-Dependent Kinases?

Hendrychová, D, Voller, J, Kryštof, V, Gucký, T, Řezníčková, E, Jorda, R

J Med Chem 2018
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
12747775 Synthesis, structure-activity relationship, and biological studies of indolocarbazoles as potent cyclin D1-CDK4 inhibitors

Faul, MM, Considine, E, Schultz, RM, Anderson, BD, Dempsey, JA, Shih, C, Spencer, CD, Conner, SE, Ogg, C, Patel, B, Li, T, Teicher, B, Brooks, HB, Campbell, RM, Zhu, G, Watkins, SA, Zhou, X

J Med Chem 2003
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
8674031 Flavopiridol induces G1 arrest with inhibition of cyclin-dependent kinase (CDK) 2 and CDK4 in human breast carcinoma cells

Worland, PJ, Sausville, EA, Carlson, BA, Dubay, MM, Brizuela, L

Cancer Res 1996
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
16476733 Inhibition of S/G2 phase CDK4 reduces mitotic fidelity

Gabrielli, B, Burgess, A, Stevens, F, Wigan, M, Gillespie, P, DePinto, W, Giles, N

J Biol Chem 2006
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
17121911 In vitro and in vivo activity of R547: a potent and selective cyclin-dependent kinase inhibitor currently in phase I clinical trials

Higgins, B, Hamid, R, Nevins, T, Heimbrook, D, Qian, H, Packman, K, Chen, Y, Hussain, S, Chu, XJ, Felix, B, Smith, M, Blain, R, Kolinsky, K, Lovey, A, Tovar, C, Goelzer, P, Xiang, Q, Luistro, L, Yin, X, DePinto, W

Mol Cancer Ther 2006
31831640 p27 allosterically activates cyclin-dependent kinase 4 and antagonizes palbociclib inhibition

Stevenson, JW, Shokat, KM, Wijeratne, TU, Witkiewicz, AK, Kumarasamy, V, Tripathi, S, Barkovich, KJ, Guiley, KZ, Knudsen, ES, Bunch, KL, Rubin, SM, Lou, K

Science 2019
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
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Authored
Orlic-Milacic, M  (2021-09-21)
Reviewed
Kadambat Nair, S  (2021-11-02)
Created
Orlic-Milacic, M  (2021-09-21)
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