625
Views
22
CrossRef citations to date
0
Altmetric
Review

Investigational drugs targeting cyclin-dependent kinases for the treatment of cancer: an update on recent findings (2013-2016)

, , , &
Pages 1215-1230 | Received 15 Mar 2016, Accepted 25 Aug 2016, Published online: 20 Sep 2016

References

  • Collins K, Jacks T, Pavletich NP. The cell cycle and cancer. Proc Natl Acad Sci U S A. 1997;94(7):2776–2778.
  • Liao Y, Feng Y, Shen J, et al. The roles and therapeutic potential of cyclin-dependent kinases (CDKs) in sarcoma. Cancer Metastasis Rev. 2015. [cited 2015 Dec 15]. DOI:10.1007/s10555-015-9601-1.
  • Murray AW. Recycling the cell cycle: cyclins revisited. Cell. 2004;116(2):221–234.
  • Malumbres M. Cyclin-dependent kinases. Genome Biol. 2014;15(6):122.
  • Malumbres M, Harlow E, Hunt T, et al. Cyclin-dependent kinases: a family portrait. Nat Cell Biol. 2009;11(11):1275–1276.
  • Lim S, Kaldis P. Cdks, cyclins and CKIs: roles beyond cell cycle regulation. Development. 2013;140(15):3079–3093.
  • Cheung ZH, Ip NY. Cdk5: a multifaceted kinase in neurodegenerative diseases. Trends Cell Biol. 2012;22(3):169–175.
  • Arif A. Extraneuronal activities and regulatory mechanisms of the atypical cyclin-dependent kinase Cdk5. Biochem Pharmacol. 2012;84(8):985–993.
  • Malumbres M, Barbacid M. To cycle or not to cycle: a critical decision in cancer. Nat Rev Cancer. 2001;1(3):222–231.
  • Jt R, Ky K, Jo B, et al. mTORC1 controls the adaptive transition of quiescent stem cells from G0 to G(Alert). Nature. 2014;510(7505):393–396.
  • Connell-Crowley L, Harper JW, Goodrich DW. Cyclin D1/Cdk4 regulates retinoblastoma protein-mediated cell cycle arrest by site-specific phosphorylation. Mol Biol Cell. 1997;8(2):287–301.
  • Dickson MA. Molecular pathways: CDK4 inhibitors for cancer therapy. Clin Cancer Res. 2014;20(13):3379–3383.
  • Santamaria D, Barriere C, Cerqueira A, et al. Cdk1 is sufficient to drive the mammalian cell cycle. Nature. 2007;448(7155):811–815.
  • Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer. 2009;9(3):153–166.
  • Malumbres M, Sotillo R, Santamaria D, et al. Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6. Cell. 2004;118(4):493–504.
  • Rzymski T, Mikula M, Wiklik K, et al. CDK8 kinase--An emerging target in targeted cancer therapy. Biochim Biophys Acta. 2015;1854(10 Pt B):1617–1629.
  • Larochelle S, Amat R, Glover-Cutter K, et al. Cyclin-dependent kinase control of the initiation-to-elongation switch of RNA polymerase II. Nat Struct Mol Biol. 2012;19(11):1108–1115.
  • Carlsten JO, Zhu X, Gustafsson CM. The multitalented mediator complex. Trends Biochem Sci. 2013;38(11):531–537.
  • Egly JM, Coin F. A history of TFIIH: two decades of molecular biology on a pivotal transcription/repair factor. DNA Repair (Amst). 2011;10(7):714–721.
  • Lapenna S, Giordano A. Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009;8(7):547–566.
  • Tigan AS, Bellutti F, Kollmann K, et al. CDK6-a review of the past and a glimpse into the future: from cell-cycle control to transcriptional regulation. Oncogene. 2015. [cited 2015 Oct 26]. DOI:10.1038/onc.2015.407.
  • Asghar U, Witkiewicz AK, Turner NC, et al. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov. 2015;14(2):130–146.
  • Peyressatre M, Prevel C, Pellerano M, et al. Targeting cyclin-dependent kinases in human cancers: from small molecules to peptide inhibitors. Cancers (Basel). 2015;7(1):179–237.
  • Morgan DO. Principles of CDK regulation. Nature. 1995;374(6518):131–134.
  • Vidula N, Rugo HS. Cyclin-dependent kinase 4/6 inhibitors for the treatment of breast cancer: a review of preclinical and clinical data. Clin Breast Cancer. 2016;16(1):8–17.
  • Choi YJ, Anders L. Signaling through cyclin D-dependent kinases. Oncogene. 2013;33(15):1890–1903.
  • Meyerson M, Harlow E. Identification of G1 kinase activity for cdk6, a novel cyclin D partner. Mol Cell Biol. 1994;14(3):2077–2086.
  • Malumbres M, Barbacid M. Mammalian cyclin-dependent kinases. Trends Biochem Sci. 2005;30(11):630–641.
  • Yu Q, Sicinska E, Geng Y, et al. Requirement for CDK4 kinase function in breast cancer. Cancer Cell. 2006;9(1):23–32.
  • Reddy HK, Mettus RV, Rane SG, et al. Cyclin-dependent kinase 4 expression is essential for neu-induced breast tumorigenesis. Cancer Res. 2005;65(22):10174–10178.
  • Schwartz R, Engel I, Fallahi-Sichani M, et al. Gene expression patterns define novel roles for E47 in cell cycle progression, cytokine-mediated signaling, and T lineage development. Proc Natl Acad Sci U S A. 2006;103(26):9976–9981.
  • Nagel S, Leich E, Quentmeier H, et al. Amplification at 7q22 targets cyclin-dependent kinase 6 in T-cell lymphoma. Leukemia. 2008;22(2):387–392.
  • Hu MG, Deshpande A, Enos M, et al. A requirement for cyclin-dependent kinase 6 in thymocyte development and tumorigenesis. Cancer Res. 2009;69(3):810–818.
  • Matushansky I, Radparvar F, Skoultchi AI. CDK6 blocks differentiation: coupling cell proliferation to the block to differentiation in leukemic cells. Oncogene. 2003;22(27):4143–4149.
  • Fujimoto T, Anderson K, Jacobsen SE, et al. Cdk6 blocks myeloid differentiation by interfering with Runx1 DNA binding and Runx1-C/EBPalpha interaction. Embo J. 2007;26(9):2361–2370.
  • Handschick K, Beuerlein K, Jurida L, et al. Cyclin-dependent kinase 6 is a chromatin-bound cofactor for NF-kappaB-dependent gene expression. Mol Cell. 2014;53(2):193–208.
  • Uras IZ, Walter GJ, Scheicher R, et al. Palbociclib treatment of FLT3-ITD+ AML cells uncovers a kinase-dependent transcriptional regulation of FLT3 and PIM1 by CDK6. Blood. 2016;127(23):2890–2902.
  • Wagner K, Damm F, Thol F, et al. FLT3-internal tandem duplication and age are the major prognostic factors in patients with relapsed acute myeloid leukemia with normal karyotype. Haematologica. 2011;96(5):681–686.
  • Kollmann K, Heller G, Schneckenleithner C, et al. A kinase-independent function of CDK6 links the cell cycle to tumor angiogenesis. Cancer Cell. 2013;24(2):167–181.
  • Scheicher R, Hoelbl-Kovacic A, Bellutti F, et al. CDK6 as a key regulator of hematopoietic and leukemic stem cell activation. Blood. 2015;125(1):90–101.
  • Placke T, Faber K, Nonami A, et al. Requirement for CDK6 in MLL-rearranged acute myeloid leukemia. Blood. 2014;124(1):13–23.
  • Lim JT, Mansukhani M, Weinstein IB. Cyclin-dependent kinase 6 associates with the androgen receptor and enhances its transcriptional activity in prostate cancer cells. Proc Natl Acad Sci U S A. 2005;102(14):5156–5161.
  • Scaltriti M, Eichhorn PJ, Cortes J, et al. Cyclin E amplification/overexpression is a mechanism of trastuzumab resistance in HER2+ breast cancer patients. Proc Natl Acad Sci U S A. 2011;108(9):3761–3766.
  • Caldon CE, Sergio CM, Kang J, et al. Cyclin E2 overexpression is associated with endocrine resistance but not insensitivity to CDK2 inhibition in human breast cancer cells. Mol Cancer Ther. 2012;11(7):1488–1499.
  • Shapiro GI. Cyclin-dependent kinase pathways as targets for cancer treatment. J Clin Oncol. 2006;24(11):1770–1783.
  • Schwartz GK, Shah MA. Targeting the cell cycle: a new approach to cancer therapy. J Clin Oncol. 2005;23(36):9408–9421.
  • Pozo K, Castro-Rivera E, Tan C, et al. The role of Cdk5 in neuroendocrine thyroid cancer. Cancer Cell. 2013;24(4):499–511.
  • Chipumuro E, Marco E, Cl C, et al. CDK7 inhibition suppresses super-enhancer-linked oncogenic transcription in MYCN-driven cancer. Cell. 2014;159(5):1126–1139.
  • Christensen CL, Kwiatkowski N, Abraham BJ, et al. Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor. Cancer Cell. 2014;26(6):909–922.
  • Kwiatkowski N, Zhang T, Rahl PB, et al. Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature. 2014;511(7511):616–620.
  • Wang Y, Zhang T, Kwiatkowski N, et al. CDK7-dependent transcriptional addiction in triple-negative breast cancer. Cell. 2015;163(1):174–186.
  • Krystof V, Baumli S, Furst R. Perspective of cyclin-dependent kinase 9 (CDK9) as a drug target. Curr Pharm Des. 2012;18(20):2883–2890.
  • Lee DK, Duan HO, Chang C. Androgen receptor interacts with the positive elongation factor P-TEFb and enhances the efficiency of transcriptional elongation. J Biol Chem. 2001;276(13):9978–9984.
  • Gordon V, Bhadel S, Wunderlich W, et al. CDK9 regulates AR promoter selectivity and cell growth through serine 81 phosphorylation. Mol Endocrinol. 2010;24(12):2267–2280.
  • Wesierska-Gadek J, Kramer MP. The impact of multi-targeted cyclin-dependent kinase inhibition in breast cancer cells: clinical implications. Expert Opin Investig Drugs. 2011;20(12):1611–1628.
  • Trowbridge JM, Rogatsky I, Garabedian MJ. Regulation of estrogen receptor transcriptional enhancement by the cyclin A/Cdk2 complex. Proc Natl Acad Sci U S A. 1997;94(19):10132–10137.
  • Rogatsky I, Trowbridge JM, Garabedian MJ. Potentiation of human estrogen receptor alpha transcriptional activation through phosphorylation of serines 104 and 106 by the cyclin A-CDK2 complex. J Biol Chem. 1999;274(32):22296–22302.
  • Wesierska-Gadek J, Mauritz M. Why (multi)targeting of cyclin-dependent kinases is a promising therapeutic option for hormone-positive breast cancer and beyond. Future Med Chem. 2016;8(1):55–72.
  • Knuesel MT, Meyer KD, Bernecky C, et al. The human CDK8 subcomplex is a molecular switch that controls mediator coactivator function. Genes Dev. 2009;23(4):439–451.
  • Firestein R, Shima K, Nosho K, et al. CDK8 expression in 470 colorectal cancers in relation to beta-catenin activation, other molecular alterations and patient survival. Int J Cancer. 2010;126(12):2863–2873.
  • Firestein R, Bass AJ, Kim SY, et al. CDK8 is a colorectal cancer oncogene that regulates beta-catenin activity. Nature. 2008;455(7212):547–551.
  • Porter DC, Farmaki E, Altilia S, et al. Cyclin-dependent kinase 8 mediates chemotherapy-induced tumor-promoting paracrine activities. Proc Natl Acad Sci U S A. 2012;109(34):13799–13804.
  • Putz EM, Gotthardt D, Hoermann G, et al. CDK8-mediated STAT1-S727 phosphorylation restrains NK cell cytotoxicity and tumor surveillance. Cell Rep. 2013;4(3):437–444.
  • Li N, Fassl A, Chick J, et al. Cyclin C is a haploinsufficient tumour suppressor. Nat Cell Biol. 2014;16(11):1080–1091.
  • Healy S, Khan P, Davie JR. Immediate early response genes and cell transformation. Pharmacol Ther. 2013;137(1):64–77.
  • Villicana C, Cruz G, Zurita M. The basal transcription machinery as a target for cancer therapy. Cancer Cell Int. 2014;14(1):18.
  • Koumenis C, Giaccia A. Transformed cells require continuous activity of RNA polymerase II to resist oncogene-induced apoptosis. Mol Cell Biol. 1997;17(12):7306–7316.
  • Bywater MJ, Poortinga G, Sanij E, et al. Inhibition of RNA polymerase I as a therapeutic strategy to promote cancer-specific activation of p53. Cancer Cell. 2012;22(1):51–65.
  • Radhakrishnan SK, Gartel AL. A novel transcriptional inhibitor induces apoptosis in tumor cells and exhibits antiangiogenic activity. Cancer Res. 2006;66(6):3264–3270.
  • Kaichi S, Takaya T, Morimoto T, et al. Cyclin-dependent kinase 9 forms a complex with GATA4 and is involved in the differentiation of mouse ES cells into cardiomyocytes. J Cell Physiol. 2011;226(1):248–254.
  • Adler AS, McCleland ML, Truong T, et al. CDK8 maintains tumor dedifferentiation and embryonic stem cell pluripotency. Cancer Res. 2012;72(8):2129–2139.
  • Derheimer FA, Chang CW, Ljungman M. Transcription inhibition: a potential strategy for cancer therapeutics. Eur J Cancer. 2005;41(16):2569–2576.
  • Wang H, Chen X, Chen Y, et al. Antitumor activity of novel chimeric peptides derived from cyclinD/CDK4 and the protein transduction domain 4. Amino Acids. 2013;44(2):499–510.
  • Bozhenko VK, Kulinich TM, Kudinova EA et al. New targeted anti CDK4/6 peptide MM-D37K. J Clin Oncol 31, 2013 (suppl; abstr e13545)
  • Novel CDK4/6 inhibitors based on P16 peptide technology platform. International Congress Targeted Anticancer Therapy 2014 final program. [ cited 2016 Mar 1] Available from: http://tatcongress.org/wp-content/uploads/2014/05/tat2014-abstracts-poster-session-2_140217.pdf
  • Losiewicz MD, Carlson BA, Kaur G, et al. Potent inhibition of CDC2 kinase activity by the flavonoid L86-8275. Biochem Biophys Res Commun. 1994;201(2):589–595.
  • Cimini A, d’Angelo M, Benedetti E, et al. Flavopiridol: an old drug with new perspectives? Implication for development of new drugs. J Cell Physiol. 2016. [cited May 2016 12]. DOI:10.1002/jcp.25421.
  • Meijer L, Borgne A, Mulner O, et al. Biochemical and cellular effects of roscovitine, a potent and selective inhibitor of the cyclin-dependent kinases cdc2, cdk2 and cdk5. Eur J Biochem. 1997;243(1–2):527–536.
  • Cicenas J, Kalyan K, Sorokinas A, et al. Roscovitine in cancer and other diseases. Ann Transl Med. 2015;3(10):135.
  • Cirstea D, Hideshima T, Santo L, et al. Small-molecule multi-targeted kinase inhibitor RGB-286638 triggers P53-dependent and -independent anti-multiple myeloma activity through inhibition of transcriptional CDKs. Leukemia. 2013;27(12):2366–2375.
  • Brasca MG, Amboldi N, Ballinari D, et al. Identification of N,1,4,4-tetramethyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-1H-py razolo[4,3-h]quinazoline-3-carboxamide (PHA-848125), a potent, orally available cyclin dependent kinase inhibitor. J Med Chem. 2009;52(16):5152–5163.
  • Degrassi A, Russo M, Nanni C, et al. Efficacy of PHA-848125, a cyclin-dependent kinase inhibitor, on the K-Ras(G12D)LA2 lung adenocarcinoma transgenic mouse model: evaluation by multimodality imaging. Mol Cancer Ther. 2010;9(3):673–681.
  • Albanese C, Alzani R, Amboldi N, et al. Anti-tumour efficacy on glioma models of PHA-848125, a multi-kinase inhibitor able to cross the blood-brain barrier. Br J Pharmacol. 2013;169(1):156–166.
  • Siemeister G, Lucking U, Am W, et al. BAY 1000394, a novel cyclin-dependent kinase inhibitor, with potent antitumor activity in mono- and in combination treatment upon oral application. Mol Cancer Ther. 2012;11(10):2265–2273.
  • Hamilton G, Klameth L, Rath B, et al. Synergism of cyclin-dependent kinase inhibitors with camptothecin derivatives in small cell lung cancer cell lines. Molecules. 2014;19(2):2077–2088.
  • Squires MS, Feltell RE, Wallis NG, et al. Biological characterization of AT7519, a small-molecule inhibitor of cyclin-dependent kinases, in human tumor cell lines. Mol Cancer Ther. 2009;8(2):324–332.
  • Chen EX, Hotte S, Hirte H, et al. A phase I study of cyclin-dependent kinase inhibitor, AT7519, in patients with advanced cancer: NCIC Clinical Trials Group IND 177. Br J Cancer. 2014;111(12):2262–2267.
  • Goh KC, Novotny-Diermayr V, Hart S, et al. TG02, a novel oral multi-kinase inhibitor of CDKs, JAK2 and FLT3 with potent anti-leukemic properties. Leukemia. 2012;26(2):236–243.
  • Tragara’s TG02 is Highly Active in CLL Cells Derived from Patients who have Failed Treatment with Ibrutinib. [cited 2016 Mar 1] Available from: http://www.tragarapharma.com/OSU%20Data%20PR%20FINAL.pdf
  • Tragara Pharmaceuticals Initiates Phase I Clinical Program for TG02. [cited 2016 Mar 1] Available from: http://www.prnewswire.com/news-releases/tragara-pharmaceuticals-initiates-phase-i-clinical-program-for-tg02-102523374.html
  • Finn RS, Aleshin A, Slamon DJ. Targeting the cyclin-dependent kinases (CDK) 4/6 in estrogen receptor-positive breast cancers. Breast Cancer Res. 2016;18(1):17.
  • Reddy MV, Akula B, Cosenza SC, et al. Discovery of 8-cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrid o[2,3-d]pyrimidine-6-carbonitrile (7x) as a potent inhibitor of cyclin-dependent kinase 4 (CDK4) and AMPK-related kinase 5 (ARK5). J Med Chem. 2014;57(3):578–599.
  • Fry DW, Harvey PJ, Keller PR, et al. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther. 2004;3(11):1427–1438.
  • Toogood PL, Harvey PJ, Repine JT, et al. Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6. J Med Chem. 2005;48(7):2388–2406.
  • FDA Approves new Indication for fulvestrant for women with HR+, HER2- metastatic breast cancer. [cited 2016 Mar 10] Available from: http://www.businesswire.com/news/home/20160302006589/en/FDA-Approves-Indication-FASLODEX%C2%AE-fulvestrant
  • Sanchez-Martinez C, Gelbert LM, Lallena MJ, et al. Cyclin dependent kinase (CDK) inhibitors as anticancer drugs. Bioorg Med Chem Lett. 2015;25(17):3420–3435.
  • Dickson MA, Tap WD, Keohan ML, et al. Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma. J Clin Oncol. 2013;31(16):2024–2028.
  • Gelbert LM, Cai S, Lin X, et al. Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine. Invest New Drugs. 2014;32(5):825–837.
  • AACR-NCI-EORTC. Symposium on molecular target and cancer therapeutics. Boston (MA): AACR; 2013. p. Abstract C88.
  • Rader J, Russell MR, Hart LS, et al. Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma. Clin Cancer Res. 2013;19(22):6173–6182.
  • Vora SR, Juric D, Kim N, et al. CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors. Cancer Cell. 2014;26(1):136–149.
  • Li C, Liu L, Liang L, et al. AMG 925 is a dual FLT3/CDK4 inhibitor with the potential to overcome FLT3 inhibitor resistance in acute myeloid leukemia. Mol Cancer Ther. 2015;14(2):375–383.
  • Li Z, Wang X, Eksterowicz J, et al. Discovery of AMG 925, a FLT3 and CDK4 dual kinase inhibitor with preferential affinity for the activated state of FLT3. J Med Chem. 2014;57(8):3430–3449.
  • Keegan K, Li C, Li Z, et al. Preclinical evaluation of AMG 925, a FLT3/CDK4 dual kinase inhibitor for treating acute myeloid leukemia. Mol Cancer Ther. 2014;13(4):880–889.
  • 105th AACR Annual Meeting. AACR annual meeting. Washington (DC): AACR; 2014. p. Abstract 4519.
  • Malinkova V, Vylicil J, Krystof V. Cyclin-dependent kinase inhibitors for cancer therapy: a patent review (2009-2014). Expert Opin Ther Pat. 2015;25(9):953–970.
  • Schiemann K, Mallinger A, Wienke D, et al. Discovery of potent and selective CDK8 inhibitors from an HSP90 pharmacophore. Bioorg Med Chem Lett. 2016;26(5):1443–1451.
  • Mallinger A, Crumpler S, Pichowicz M, et al. Discovery of potent, orally bioavailable, small-molecule inhibitors of WNT signaling from a cell-based pathway screen. J Med Chem. 2015;58(4):1717–1735.
  • Rzymski T, Zarebski A, Dreas A, et al. Substituted tricyclic benzimidazoles as kinase inhibitor. WO2014072435 (2014)
  • Robinson IB, Porter DC, Wentland MP Cdk8/cdk19 selective inhibitors and their use in antimetastatic and chemopreventative methods for cancer. WO2013116786 (2013)
  • Broude E, Roninson IB Inhibitors of cdk8/19 for use in treating estrogen receptor positive breast cancer. WO2014134169 (2014)
  • Cai D, Latham VM Jr., Zhang X, et al. Combined depletion of cell cycle and transcriptional cyclin-dependent kinase activities induces apoptosis in cancer cells. Cancer Res. 2006;66(18):9270–9280.
  • Kaelin WG Jr. The concept of synthetic lethality in the context of anticancer therapy. Nat Rev Cancer. 2005;5(9):689–698.
  • Liu Y, Zhu YH, Mao CQ, et al. Triple negative breast cancer therapy with CDK1 siRNA delivered by cationic lipid assisted PEG-PLA nanoparticles. J Control Release. 2014;192:114–121.
  • Huang CH, Lujambio A, Zuber J, et al. CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma. Genes Dev. 2014;28(16):1800–1814.
  • Bommi-Reddy A, Almeciga I, Sawyer J, et al. Kinase requirements in human cells: III. Altered kinase requirements in VHL-/- cancer cells detected in a pilot synthetic lethal screen. Proc Natl Acad Sci U S A. 2008;105(43):16484–16489.
  • Espacenet, free european patent database search engine. [cited 2016 Mar 10] Available from: http://worldwide.espacenet.com

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.