284
Views
0
CrossRef citations to date
0
Altmetric
Review

Recent Progress of Cyclin-Dependent Kinase Inhibitors as Potential Anticancer Agents

, , , , &
Pages 2047-2076 | Received 18 Jun 2016, Accepted 18 Aug 2016, Published online: 24 Oct 2016

References

  • Norbury C , NurseP. Animal cell cycles and their control. Annu. Rev. Biochem.61 (8), 441–470 (1992).
  • Malumbres M , BarbacidM. To cycle or not to cycle: a critical decision in cancer. Nat. Rev. Cancer1 (3), 222–231 (2001).
  • Koepp DM , HarperJW, ElledgeSJ. How the cyclin became a cyclin. Cell97 (4), 431–434 (1999).
  • Cao L , ChenF, YangXet al. Phylogenetic analysis of CDK and cyclin proteins in premetazoan lineages. BMC Evol. Biol.14 (1), 1–16 (2014).
  • Malumbres M , HarlowE, HuntTet al. Cyclin-dependent kinases: a family portrait. Nat. Cell Biol.11 (11), 1275–1276 (2009).
  • Sherr CJ , RobertsJM. Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev.9 (10), 1149–1163 (1995).
  • Baumli S , LolliG, LoweEDet al. The structure of P-TEFb (CDK9/cyclin T1), its complex with flavopiridol and regulation by phosphorylation. EMBO J.27 (13), 1907–1918 (2008).
  • Brown NR , KorolchukS, MartinMPet al. CDK1 structures reveal conserved and unique features of the essential cell cycle CDK. Nat. Commun.6, 6769 (2015).
  • Lim S , KaldisP. Cdks, cyclins and CKIs: roles beyond cell cycle regulation. Development140 (15), 3079–3093 (2013).
  • Malumbres M . Cyclin-dependent kinases. Genome Biol.15 (6), 122 (2014).
  • Uniprot . http://www.uniprot.org/.
  • Lolli G . Structural dissection of cyclin dependent kinases regulation and protein recognition properties. Cell Cycle9 (8), 1551–1561 (2010).
  • Echalier A , EndicottJA, NobleMEM. Recent developments in cyclin-dependent kinase biochemical and structural studies. Biochim. Biophys. Acta1804 (3), 511–519 (2010).
  • Echalier A , HoleAJ, LolliGet al. An inhibitor's-eye view of the ATP-binding site of CDKs in different regulatory states. ACS Chem. Biol.9 (6), 1251–1256 (2014).
  • Lundberg AS , WeinbergRA. Functional inactivation of the retinoblastoma protein requires sequential modification by at least two distinct cyclin-CDK complexes. Mol. Cell. Biol.18 (2), 753–761 (1998).
  • Sherr CJ . The Pezcoller lecture: cancer cell cycles revisited. Cancer Res.60 (14), 3689–3695 (2000).
  • Ford HL , PardeeAB. The S phase: beginning, middle, and end: a perspective. J. Cell. Biochem. Suppl.30–31, 1–7 (1998).
  • Santamaría D , BarrièreC, CerqueiraAet al. Cdk1 is sufficient to drive the mammalian cell cycle. Nature448 (7155), 811–815 (2007).
  • Barnett DGS , BibbJA. The role of Cdk5 in cognition and neuropsychiatric and neurological pathology. Brain Res Bull.85 (1–2), 9–13 (2011).
  • Fisher RP . Secrets of a double agent: CDK7 in cell-cycle control and transcription. J. Cell Sci.118 (22), 5171–5180 (2005).
  • Larochelle S , BatlinerJ, GambleMJet al. Dichotomous but stringent substrate selection by the dual-function Cdk7 complex revealed by chemical genetics. Nat. Struct. Mol. Biol.13 (1), 55–62 (2006).
  • Belakavadi M , FondellJD. Cyclin-dependent kinase 8 positively cooperates with mediator to promote thyroid hormone receptor-dependent transcriptional activation. Mol. Cell. Biol.30 (10), 2437–2448 (2010).
  • Donner AJ , EbmeierCC, TaatjesDJet al. CDK8 is a positive regulator of transcriptional elongation within the serum response network. Nat. Struct. Mol. Biol.17 (2), 194–201 (2010).
  • Firestein R , BassAJ, KimSYet al. CDK8 is a colorectal cancer oncogene that regulates β-catenin activity. Nature455 (7212), 547–551 (2008).
  • Morris EJ , JiJ-Y, YangFet al. E2F1 represses β-catenin transcription and is antagonized by both pRB and CDK8. Nature455 (7212), 552–556 (2008).
  • Garriga J , XieH, ObradovicZet al. Selective control of gene expression by CDK9 in human cells. J. Cell. Physiol.222 (1), 200–208 (2010).
  • Cen L , CarlsonBL, SchroederMAet al. P16-Cdk4-Rb axis controls sensitivity to a cyclin-dependent kinase inhibitor PD0332991 in glioblastoma xenograft cells. Neuro Oncol.14 (7), 870–881 (2012).
  • Roy PG , ThompsonAM. Cyclin D1 and breast cancer. Breast15 (6), 718–727 (2006).
  • Asghar U , WitkiewiczAK, TurnerNCet al. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat. Rev. Drug Discov.14 (2), 130–146 (2015).
  • Paternot S , BockstaeleL, BisteauXet al. Rb inactivation in cell cycle and cancer: the puzzle of highly regulated activating phosphorylation of CDK4 versus constitutively active CDK-activating kinase. Cell Cycle9 (4), 689–699 (2010).
  • Park S , LeeJ, DoI-Get al. Aberrant CDK4 amplification in refractory rhabdomyosarcoma as identified by genomic profiling. Sci. Rep.4 (1), 3623 (2014).
  • Poomsawat S , BuajeebW, KhovidhunkitSet al. Alteration in the expression of CDK4 and CDK6 proteins in oral cancer and premalignant lesions. J. Oral Pathol. Med.39 (10), 793–799 (2010).
  • Malumbres M . Therapeutic opportunities to control tumor cell cycles. Clin. Transl. Oncol.8 (6), 399–408 (2006).
  • Krystof V , BaumliS, FurstR. Perspective of cyclin-dependent kinase 9 (CDK9) as a drug target. Curr. Pharm. Des.18 (20), 2883–2890 (2012).
  • Romano G . Deregulations in the cyclin-dependent kinase-9-related pathway in cancer: implications for drug discovery and development. ISRN Oncol.2013 (9), 1–14 (2013).
  • Parker B , CarlsonB, SmithAet al. Flavopiridol (L86 8275; NSC 649890), a new kinase inhibitor for tumor therapy. Int. J. Oncol.9 (6), 1143–1168 (1996).
  • Shapiro GI . Preclinical and clinical development of the cyclin-dependent kinase inhibitor flavopiridol. Clin. Cancer Res.10 (12), S4270–S4275 (2004).
  • Sedlacek HH . Mechanisms of action of flavopiridol. Crit. Rev. Oncol. Hematol.38 (2), 139–170 (2001).
  • Mahoney E , LucasDM, GuptaSVet al. ER stress and autophagy: new discoveries in the mechanism of action and drug resistance of the cyclin-dependent kinase inhibitor flavopiridol. Blood120 (6), 1262–1273 (2012).
  • Hofmeister CC , PoiM, BowersMAet al. A Phase I trial of flavopiridol in relapsed multiple myeloma. Cancer Chemother. Pharmacol.73 (2), 249–257 (2014).
  • Liu N-A , JiangH, Ben-ShlomoAet al. Targeting zebrafish and murine pituitary corticotroph tumors with a cyclin-dependent kinase (CDK) inhibitor. Proc. Natl Acad. Sci. USA108 (20), 8414–8419 (2011).
  • Kumar SK , LaPlantB, ChngWJet al. Dinaciclib, a novel CDK inhibitor, demonstrates encouraging single-agent activity in patients with relapsed multiple myeloma. Blood.125 (3), 443–448 (2015).
  • Seftel MD , FrcpcM, KuruvillaJet al. A Phase II study of AT7519M, a CDK inhibitor, in patients with chronic lymphocytic leukemia: NCIC CTG trial IND.193. Blood.124 (21), 5670 (2014).
  • Goh KC , Novotny-DiermayrV, HartSet al. TG02, a novel oral multi-kinase inhibitor of CDKs, JAK2 and FLT3 with potent anti-leukemic properties. Leukemia26 (2), 236–243 (2012).
  • Benouaich-Amiel A , MazzaE, MassardCet al. Phase I study of the oral CDK-TRKA inhibitor PHA-848125 in recurrent malignant glioma (MG). (Meeting abstracts). J. Clin. Oncol.28 (Suppl.), Abstract 2087 (2010).
  • Grilley-Olson JE , WeissGJ, RajagopalanPet al. A dose-escalation Phase I study of oral pan-CDK inhibitor BAY 1000394 in patients with advanced solid tumors: dose escalation with an intermittent 28 days on/14 days off schedule. (Meeting abstracts). J. Clin. Oncol.30 (Suppl.), Abstract 3046 (2012).
  • Clark AS , KarasicTB, DeMicheleAet al. Palbociclib (PD0332991) – a selective and potent cyclin-dependent kinase inhibitor. JAMA Oncol.2 (2), 253 (2016).
  • DeMichele A , ClarkAS, TanKSet al. CDK 4/6 inhibitor palbociclib (PD0332991) in Rb+ advanced breast cancer: Phase II activity, safety, and predictive biomarker assessment. Clin. Cancer Res.21 (5), 995–1001 (2015).
  • Infante JR , ShapiroGI, WitteveenPOet al. Abstract A276: Phase 1 multicenter, open label, dose-escalation study of LEE011, an oral inhibitor of cyclin-dependent kinase 4/6, in patients with advanced solid tumors or lymphomas. (Meeting abstracts). Mol. Cancer Ther.12 (Suppl. 11), A276 (2013).
  • Infante JR , ShapiroG, WitteveenPet al. A Phase I study of the single-agent CDK4/6 inhibitor LEE011 in pts with advanced solid tumors and lymphomas. (Meeting abstracts). J. Clin. Oncol.32 (Suppl.), Abstract 2528 (2014).
  • Munster PN , HamiltonEP, FranklinCet al. Phase lb study of LEE011 and BYL719 in combination with letrozole in estrogen receptor-positive, HER2-negative breast cancer (ER+, HER2-BC). (Meeting abstracts). J. Clin. Oncol.32 (Suppl.), Abstract 533 (2014).
  • Tripathy D , BardiaA, HurvitzSAet al. Phase III, randomized, double-blind, placebo-controlled study of ribociclib (LEE011) in combination with either tamoxifen and goserelin or a non-steroidal aromatase inhibitor (NSAI) and goserelin for the treatment of premenopausal women with HR+, HER2- advanced breast cancer (aBC): MONALEESA-7. (Meeting abstracts). J. Clin. Oncol.33 (Suppl.), Abstract TPS625 (2015).
  • Muranen T , Meric-BernstamF, MillsGB. Promising rationally derived combination therapy with PI3K and CDK4/6 inhibitors. Cancer Cell.26 (1), 7–9 (2014).
  • Goldman JW , ShiP, ReckMet al. Treatment rationale and study design for the JUNIPER study: a randomized Phase III study of abemaciclib with best supportive care versus erlotinib with best supportive care in patients with stage IV non-small-cell lung cancer with a detectable KRAS mutati. Clin. Lung Cancer17 (1), 80–84 (2016).
  • Bisi JE , SorrentinoJA, RobertsPJet al. Preclinical characterization of G1T28: a novel CDK4/6 inhibitor for reduction of chemotherapy-induced myelosuppression. Mol. Cancer Ther.15 (5), 783–793 (2016).
  • Chao SH . Flavopiridol inactivates P-TEFb and blocks most RNA polymerase II transcription in vivo. J. Biol. Chem.276 (34), 31793–31799 (2001).
  • Jain SK , BharateSB, VishwakarmaRA. Cyclin-dependent kinase inhibition by flavoalkaloids. Mini-Reviews Med. Chem.12 (7), 632–649 (2012).
  • Meijer L , BorgneA, MulnerOet al. Biochemical and cellular effects of roscovitine, a potent and selective inhibitor of the cyclin-dependent kinases CDC2, CDK2 and CDK5. Eur. J. Biochem.243 (1–2), 527–536 (1997).
  • McClue SJ , BlakeD, ClarkeRet al. In vitro and in vivo antitumor properties of the cyclin dependent kinase inhibitor CYC202 (R-roscovitine). Int. J. Cancer102 (5), 463–468 (2002).
  • Hahntow IN , SchnellerF, OelsnerMet al. Cyclin-dependent kinase inhibitor roscovitine induces apoptosis in chronic lymphocytic leukemia cells. Leukemia18 (4), 747–755 (2004).
  • Cyclacel & ManRos Therapeutics announce licensing & supply agreement regarding development of seliciclib in cystic fibrosis. http://investor.cyclacel.com/releasedetail.cfm?ReleaseID=919756.
  • Wilson SC , AtrashB, BarlowCet al. Design, synthesis and biological evaluation of 6-pyridylmethylaminopurines as CDK inhibitors. Bioorganic Med. Chem.19 (22), 6949–6965 (2011).
  • Kawakami M , MustachioLM, LiuXet al. Abstract 942: novel CDK2/9 inhibitor has antineoplastic activity in lung cancer by inducing anaphase catastrophe. (Meeting Abstracts). Cancer Res.75 (Suppl. 15), 942 (2015).
  • Bettayeb K , OumataN, EchalierAet al. CR8, a potent and selective, roscovitine-derived inhibitor of cyclin-dependent kinases. Oncogene27 (44), 5797–5807 (2008).
  • Kabadi SV , StoicaBA, HanscomMet al. CR8, a selective and potent CDK inhibitor, provides neuroprotection in experimental traumatic brain injury. Neurotherapeutics9 (2), 405–421 (2012).
  • Gucký T , JordaR, ZatloukalMet al. A novel series of highly potent 2,6,9-trisubstituted purine cyclin-dependent kinase inhibitors. J. Med. Chem.56 (15), 6234–6247 (2013).
  • Jorda R , ParuchK, KrystofV. Cyclin-dependent kinase inhibitors inspired by roscovitine: purine bioisosteres. Curr. Pharm. Des.18 (20), 2974–2980 (2012).
  • Parry D , GuziT, ShanahanFet al. Dinaciclib (SCH 727965), a novel and potent cyclin-dependent kinase inhibitor. Mol. Cancer Ther.9 (8), 2344–2353 (2010).
  • Paruch K , DwyerMP, AlvarezCet al. Discovery of Dinaciclib (SCH 727965): a potent and selective inhibitor of cyclin-dependent kinases. ACS Med. Chem. Lett.1 (5), 204–208 (2010).
  • Martin MP , OlesenSH, GeorgGIet al. Cyclin-dependent kinase inhibitor dinaciclib interacts with the acetyl-lysine recognition site of bromodomains. ACS Chem. Biol.8 (11), 2360–2365 (2013).
  • Squires MS , FeltellRE, WallisNGet al. Biological characterization of AT7519, a small-molecule inhibitor of cyclin-dependent kinases, in human tumor cell lines. Mol. Cancer Ther.8 (2), 324–332 (2009).
  • Dolman MEM , PoonE, EbusMEet al. Cyclin-dependent kinase inhibitor AT7519 as a potential drug for MYCN-dependent neuroblastoma. Clin. Cancer Res.21 (22), 5100–5109 (2015).
  • Wyatt PG , WoodheadAJ, BerdiniVet al. Identification of N-(4-piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide (AT7519), a novel cyclin dependent kinase inhibitor using fragment-based x-ray crystallography and structure based drug design. J. Med. Chem.51 (16), 4986–4999 (2008).
  • Byth KF , ThomasA, HughesGet al. AZD5438, a potent oral inhibitor of cyclin-dependent kinases 1, 2, and 9, leads to pharmacodynamic changes and potent antitumor effects in human tumor xenografts. Mol. Cancer Ther.8 (7), 1856–1866 (2009).
  • Jones CD , AndrewsDM, BarkerAJet al. The discovery of AZD5597, a potent imidazole pyrimidine amide CDK inhibitor suitable for intravenous dosing. Bioorg. Med. Chem. Lett.18 (24), 6369–6373 (2008).
  • Boss DS , SchwartzGK, MiddletonMRet al. Safety, tolerability, pharmacokinetics and pharmacodynamics of the oral cyclin-dependent kinase inhibitor AZD5438 when administered at intermittent and continuous dosing schedules in patients with advanced solid tumours. Ann. Oncol.21 (4), 884–894 (2009).
  • Raghavan P , TumatiV, YuLet al. AZD5438, an inhibitor of Cdk1, 2, and 9, enhances the radiosensitivity of non-small cell lung carcinoma cells. Int. J. Radiat. Oncol. Biol. Phys.84 (4), e507–e514 (2012).
  • Wang S , MeadesC, WoodGet al. 2-Anilino-4-(thiazol-5-yl)pyrimidine CDK inhibitors: synthesis, SAR analysis, x-ray crystallography, and biological activity. J. Med. Chem.47 (7), 1662–1675 (2004).
  • Liu X , ShiS, LamF, PepperC, FischerPM, WangS. CDKI-71, a novel CDK9 inhibitor, is preferentially cytotoxic to cancer cells compared with flavopiridol. Int. J. Cancer130 (5), 1216–1226 (2012).
  • Scott EN , ThomasAL, MolifeLRet al. A Phase I dose escalation study of the pharmacokinetics and tolerability of ZK 304709, an oral multi-targeted growth inhibitor (MTGI™), in patients with advanced solid tumours. Cancer Chemother. Pharmacol.64 (2), 425–429 (2009).
  • Lücking U , JautelatR, KrügerMet al. The lab oddity prevails: discovery of pan-CDK inhibitor (R)-S-Cyclopropyl-S-(4-{[4-{[(1R,2R)-2-hydroxy-1-methylpropyl]oxy}-5-(trifluoromethyl) pyrimidin-2-yl]amino}phenyl)sulfoximide (BAY 1000394) for the treatment of cancer. ChemMedChem8 (7), 1067–1085 (2013).
  • Ayaz P , AndresD, KwiatkowskiDAet al. Conformational adaption may explain the slow dissociation kinetics of roniciclib (BAY 1000394), a type I CDK inhibitor with kinetic selectivity for CDK2 and CDK9. ACS Chem. Biol.11 (6), 1710–1719 (2016).
  • Siemeister G , LückingU, WengnerAMet 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.11 (10), 2265–2273 (2012).
  • Brasca MG , AmboldiN, BallinariDet al. Identification of N,1,4,4-Tetramethyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-1H -pyrazolo[4,3-h]quinazoline-3-carboxamide (PHA-848125), a potent, orally available cyclin dependent kinase inhibitor. J. Med. Chem.52 (16), 5152–5163 (2009).
  • Brasca MG , AlbaneseC, AlzaniRet al. Optimization of 6,6-dimethyl pyrrolo[3,4-c]pyrazoles: identification of PHA-793887, a potent CDK inhibitor suitable for intravenous dosing. Bioorg. Med. Chem.18 (5), 1844–1853 (2010).
  • Massard C , SoriaJC, AnthoneyDAet al. A first in man, Phase I dose-escalation study of PHA-793887, an inhibitor of multiple cyclin-dependent kinases (CDK2, 1 and 4) reveals unexpected hepatotoxicity in patients with solid tumors. Cell Cycle10 (6), 963–970 (2011).
  • Berthet C , AleemE, CoppolaVet al. CDK2 knockout mice are viable. Curr. Biol.13 (20), 1775–1785 (2003).
  • Tetsu O , McCormickF. Proliferation of cancer cells despite CDK2 inhibition. Cancer Cell3 (3), 233–245 (2003).
  • Merrick KA , WohlboldL, ZhangCet al. Switching CDK2 on or off with small molecules to reveal requirements in human cell proliferation. Mol. Cell42 (5), 624–636 (2011).
  • Horiuchi D , E HuskeyN, KusdraLet al. Chemical–genetic analysis of cyclin dependent kinase 2 function reveals an important role in cellular transformation by multiple oncogenic pathways. Proc. Natl Acad. Sci. USA109 (17), E1019–E1027 (2012).
  • Etemadmoghadam D , WeirBA, Au-YeungGet al. Synthetic lethality between CCNE1 amplification and loss of BRCA1. Proc. Natl Acad. Sci. USA110 (48), 19489–19494 (2013).
  • Etemadmoghadam D , Au-YeungG, WallMet al. Resistance to CDK2 inhibitors is associated with selection of polyploid cells in CCNE1-amplified ovarian cancer. Clin. Cancer Res.19 (21), 5960–5971 (2013).
  • Byth KF , CulshawJD, GreenSet al. Imidazo[1,2-a]pyridines. Part 2: SAR and optimisation of a potent and selective class of cyclin-dependent kinase inhibitors. Bioorganic Med. Chem. Lett.14 (9), 2245–2248 (2004).
  • Byth KF , CooperN, CulshawJDet al. Imidazo[1,2-b]pyridazines: a potent and selective class of cyclin-dependent kinase inhibitors. Bioorganic Med. Chem. Lett.14 (9), 2249–2252 (2004).
  • Marchetti F , CanoC, CurtinNJet al. Synthesis and biological evaluation of 5-substituted O4-alkylpyrimidines as CDK2 inhibitors. Org. Biomol. Chem.8 (10), 2397–2407 (2010).
  • Anscombe E , MeschiniE, Mora-VidalRet al. Identification and characterization of an irreversible inhibitor of CDK2. Chem. Biol.22 (9), 1159–1164 (2015).
  • Dickson MA . Molecular pathways: CDK4 inhibitors for cancer therapy. Clin. Cancer Res.20 (13), 3379–3383 (2014).
  • Cho YS , BorlandM, BrainCet al. 4-(Pyrazol-4-yl)-pyrimidines as selective inhibitors of cyclin-dependent kinase 4/6. J. Med. Chem.53 (22), 7938–7957 (2010).
  • Cho YS , AngoveH, BrainCet al. Fragment-based discovery of 7-azabenzimidazoles as potent, highly selective, and orally active CDK4/6 inhibitors. ACS Med. Chem. Lett.3 (6), 445–449 (2012).
  • VanderWel SN , HarveyPJ, McNamaraDJet al. Pyrido[2,3-d]pyrimidin-7-ones as specific inhibitors of cyclin-dependent kinase 4. J. Med. Chem.48 (7), 2371–2387 (2005).
  • Toogood PL , HarveyPJ, RepineJTet al. Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6. J. Med. Chem.48 (7), 2388–2406 (2005).
  • Sherr CJ , BeachD, ShapiroGI. Targeting CDK4 and CDK6: from discovery to therapy. Cancer Discov.6 (4), 353–367 (2015).
  • Rader J , RussellMR, HartLSet al. Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma. Clin. Cancer Res.19 (22), 6173–6182 (2013).
  • Gelbert LM , CaiS, LinXet 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.32 (5), 825–837 (2014).
  • Llombart A , ToiM, KliseSRet al. A Phase III study of abemaciclib (LY2835219) combined with fulvestrant in women with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer (MONARCH 2). Cancer Res.75 (9 Suppl.), Abstract OT1–1–07 (2015).
  • Roberts PJ , BisiJE, StrumJCet al. Multiple roles of cyclin-dependent kinase 4/6 inhibitors in cancer therapy. J. Natl Cancer Inst.104 (6), 476–487 (2012).
  • Sorrentino JA , HeS, BisiJEet al. Abstract 941: G1T28-1, a novel CDK4/6 inhibitor, protects murine hematopoietic stem and progenitor cells from cytotoxic chemotherapy. (Meeting abstracts). Cancer Res.75 (Suppl. 15), 941 (2015).
  • Tiessen RG , RobertsPJ, SorrentinoJAet al. First-in-human Phase 1 safety, PK, and PD study of the CDK4/6 inhibitor G1T28. (Meeting abstracts). J. Clin. Oncol.33 (Suppl.), Abstract 2527 (2015).
  • Herrera-Abreu MT , PalafoxM, AsgharUet al. Early adaptation and acquired resistance to CDK4/6 inhibition in estrogen receptor-positive breast cancer. Cancer Res.76 (8), 2301–2313 (2016).
  • Węsierska-Gądek J , MauritzM. Why (multi)targeting of cyclin-dependent kinases is a promising therapeutic option for hormone-positive breast cancer and beyond. Future Med. Chem.8 (1), 55–72 (2016).
  • Reddy MVR , AkulaB, CosenzaSCet al. Discovery of 8-cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[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.57 (3), 578–599 (2014).
  • Perumal D , KuoP-Y, LeshchenkoVVet al. Dual targeting of CDK4 and ARK5 using a novel kinase inhibitor ON123300 exerts potent anticancer activity against multiple myeloma. Cancer Res.76 (5), 1225–1236 (2016).
  • Li Z , WangX, EksterowiczJet al. Discovery of AMG 925, a FLT3 and CDK4 dual kinase inhibitor with preferential affinity for the activated state of FLT3. J. Med. Chem.57 (8), 3430–3449 (2014).
  • Sonawane YA , TaylorMA, NapoleonJVet al. Cyclin dependent kinase 9 inhibitors for cancer therapy. J. Med. Chem. doi: 10.1021/acs.jmedchem.6b00150 (2016) ( Epub ahead of print).
  • Wang ZQ , JohnsonCL, KumarAet al. Inhibition of P-TEFb by DRB suppresses SIRT1/CK2α pathway and enhances radiosensitivity of human cancer cells. Anticancer Res.34 (12), 6981–6989 (2014).
  • Huang CH , LujambioA, ZuberJet al. CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma. Genes Dev.28 (16), 1800–1814 (2014).
  • Lemke J , KarstedtSV, HayMAEet al. Selective CDK9 inhibition overcomes TRAIL resistance by concomitant suppression of cFlip and Mcl-1. Cell Death Differ.21 (3), 491–502 (2014).
  • Lam F , AbbasAY, ShaoHet al. Targeting RNA transcription and translation in ovarian cancer cells with pharmacological inhibitor CDKI-73. Oncotarget5 (17), 7691–7704 (2014).
  • Walsby E , PrattG, ShaoHet al. A novel Cdk9 inhibitor preferentially targets tumor cells and synergizes with fludarabine. Oncotarget5 (2), 375–385 (2014).
  • Storch K , CordesN. The impact of CDK9 on radiosensitivity, DNA damage repair and cell cycling of HNSCC cancer cells. Int. J. Oncol.48 (1), 191–198 (2016).
  • Chen R . Transcription inhibition by flavopiridol: mechanism of chronic lymphocytic leukemia cell death. Blood106 (7), 2513–2519 (2005).
  • MacCallum DE . Seliciclib (CYC202, R-Roscovitine) induces cell death in multiple myeloma cells by inhibition of RNA polymerase II-dependent transcription and down-regulation of Mcl-1. Cancer Res.65 (12), 5399–5407 (2005).
  • Santo L , ValletS, HideshimaTet al. AT7519, A novel small molecule multi-cyclin-dependent kinase inhibitor, induces apoptosis in multiple myeloma via GSK-3β activation and RNA polymerase II inhibition. Oncogene29 (16), 2325–2336 (2010).
  • Gregory GP , HoggSJ, KatsLMet al. CDK9 inhibition by dinaciclib potently suppresses Mcl-1 to induce durable apoptotic responses in aggressive MYC-driven B-cell lymphoma in vivo. Leukemia29 (6), 1437–1441 (2015).
  • Wang S , FischerPM. Cyclin-dependent kinase 9: a key transcriptional regulator and potential drug target in oncology, virology and cardiology. Trends Pharmacol. Sci.29 (6), 302–313 (2008).
  • Turinetto V , PorceddaP, OrlandoLet al. The cyclin-dependent kinase inhibitor 5, 6-dichloro-1-beta-D-ribofuranosylbenzimidazole induces nongenotoxic, DNA replication-independent apoptosis of normal and leukemic cells, regardless of their p53 status. BMC Cancer9 (1), 281 (2009).
  • Baumli S , EndicottJA, JohnsonLN. Halogen bonds form the basis for selective P-TEFb inhibition by DRB. Chem. Biol.17 (9), 931–936 (2010).
  • Kryštof V , CankařP, FryšováIet al. 4-Arylazo-3, 5-diamino-1H-pyrazole CDK inhibitors: SAR study, crystal structure in complex with CDK2, selectivity, and cellular effects. J. Med. Chem.49 (22), 6500–6509 (2006).
  • Baumli S , HoleAJ, NobleMEMet al. The CDK9 C-helix exhibits conformational plasticity that may explain the selectivity of CAN508. ACS Chem. Biol.7 (5), 811–816 (2012).
  • Kryštof V , RárováL, LieblJet al. The selective P-TEFb inhibitor CAN508 targets angiogenesis. Eur. J. Med. Chem.46 (9), 4289–4294 (2011).
  • Wang S , GriffithsG, MidgleyCAet al. Discovery and characterization of 2-anilino-4-(thiazol-5-yl)pyrimidine transcriptional CDK inhibitors as anticancer agents. Chem. Biol.17 (10), 1111–1121 (2010).
  • Shao H , ShiS, FoleyDWet al. Synthesis, structure–activity relationship and biological evaluation of 2,4,5-trisubstituted pyrimidine CDK inhibitors as potential anti-tumour agents. Eur. J. Med. Chem.70, 447–455 (2013).
  • Shao H , ShiS, HuangSet al. Substituted 4-(thiazol-5-yl)-2-(phenylamino)pyrimidines are highly active CDK9 inhibitors: synthesis, x-ray crystal structures, structure-activity relationship, and anticancer activities. J. Med. Chem.56 (3), 640–659 (2013).
  • Hole AJ , BaumliS, ShaoHet al. Comparative structural and functional studies of 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile CDK9 inhibitors suggest the basis for isotype selectivity. J. Med. Chem.56 (3), 660–670 (2013).
  • Ingenium Pharmaceuticals, GmbH: WO2008129080 (2008).
  • Albert TK , RigaultC, EickhoffJet al. Characterization of molecular and cellular functions of the cyclin-dependent kinase CDK9 using a novel specific inhibitor. Br. J. Pharmacol.171 (1), 55–68 (2014).
  • Németh G , VargaZ, GreffZet al. Novel, selective CDK9 inhibitors for the treatment of HIV infection. Curr. Med. Chem.18 (3), 342–358 (2011).
  • Németh G , GreffZ, SiposAet al. Synthesis and evaluation of phosphorus containing, specific CDK9/CycT1 inhibitors. J. Med. Chem.57 (10), 3939–3965 (2014).
  • Yin T , LallenaMJ, KreklauELet al. A novel CDK9 inhibitor shows potent antitumor efficacy in preclinical hematologic tumor models. Mol. Cancer Ther.13 (6), 1442–1456 (2014).
  • Echalier A , HoleAJ, LolliGet al. An inhibitor's-eye view of the ATP-binding site of CDKs in different regulatory states. ACS Chem. Biol.9 (6), 1251–1256 (2014).
  • Abate AA , PentimalliF, EspositoLet al. ATP-noncompetitive CDK inhibitors for cancer therapy: an overview. Expert Opin. Investig. Drugs22 (7), 895–906 (2013).
  • Betzi S , AlamR, MartinMet al. Discovery of a potential allosteric ligand binding site in CDK2. ACS Chem. Biol.6 (5), 492–501 (2011).
  • Rastelli G , AnighoroA, ChripkovaMet al. Structure-based discovery of the first allosteric inhibitors of cyclin-dependent kinase 2. Cell Cycle13 (14), 2296–2305 (2014).
  • Bozhenko VK , KulinichTM, KudinovaEAet al. New targeted anti CDK4/6 peptide MM-D37K. (Meeting abstracts). J. Clin. Oncol.31 (Suppl.), Abstract 3545 (2013).
  • Van Herpen C , PostowMA, CarlinoMSet al. 3300 A Phase 1b/2 study of ribociclib (LEE011; CDK4/6 inhibitor) in combination with binimetinib (MEK162; MEK inhibitor) in patients with NRAS-mutant melanoma. Eur. J. Cancer.51, S663 (2015).
  • Ku BM , KohJ, BaeYHet al. The CDK4/6 inhibitor has potent activity in combination with mTOR inhibitor in head and neck squamous cell carcinoma. (Meeting abstracts). Cancer Res.76 (Suppl. 14), Abstract 2837 (2016).
  • Vora SR , JuricD, KimNet al. CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors. Cancer Cell.26 (1), 136–149 (2014).
  • Hu C , DadonT, ChennaVet al. Combined inhibition of cyclin-dependent kinases (dinaciclib) and AKT (MK-2206) blocks pancreatic tumor growth and metastases in patient-derived xenograft models. Mol. Cancer Ther.14 (7), 1532–1539 (2015).
  • Bahr BL , MaughanKS, SohKKet al. Combination strategies to target super enhancer transcriptional activity by CDK9 and BRD4 inhibition in acute myeloid leukemia. (Meeting abstracts). Cancer Res.75 (Suppl. 15), Abstract 2698 (2015).
  • Pogorelčnik B , BrvarM, ŽeguraBet al. Discovery of mono- and disubstituted 1H-Pyrazolo[3,4]pyrimidines and 9H-Purines as catalytic inhibitors of human DNA topoisomerase IIα. ChemMedChem10 (2), 345–359 (2015).
  • Errico A . Breast cancer: PALOMA-3 confirms that CDK4/6 is a key therapeutic target. Nat. Rev. Clin. Oncol.12 (8), 436 (2015).
  • Finn RS , CrownJP, LangIet al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised Phase 2 study. Lancet Oncol.16 (1), 25–35 (2015).

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.