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Dinaciclib

Description of Dinaciclib: Dinaciclib is a CDK inhibitore, is also  a pyrazolo[1,5-a]pyrimidine with potential antineoplastic activity. Dinaciclib selectively inhibits cyclin dependent kinases CDK1, CDK2, CDK5, and CDK9; inhibition of CDK1 and CDK2 may result in cell cycle repression and tumor cell apoptosis. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:     Schering-Plough/Merck

Dinaciclib inhibits CDK2, CDK5, CDK1, and CDK9 activity in vitro with IC(50) values of 1, 1, 3, and 4 nmol/L, respectively. SCH 727965 was selected as a clinical candidate using a functional screen in vivo that integrated both efficacy and safety parameters. Compared with flavopiridol, SCH 727965 exhibits superior activity with an improved therapeutic index. In cell-based assays, SCH 727965 completely suppressed retinoblastoma phosphorylation, which correlated with apoptosis onset and total inhibition of bromodeoxyuridine incorporation in >100 tumor cell lines of diverse origin and background. Moreover, short exposures to SCH 727965 were sufficient for long-lasting cellular effects. SCH 727965 induced regression of established solid tumors in a range of mouse models following intermittent scheduling of doses below the maximally tolerated level. This was associated with modulation of pharmacodynamic biomarkers in skin punch biopsies and rapidly reversible, mechanism-based effects on hematologic parameters. These results suggest that SCH 727965 is a potent and selective CDK inhibitor and a novel cytotoxic agent. (source: Mol Cancer Ther. 2010 Aug;9(8):2344-53. Epub 2010 Jul 27).

Dinaciclib (SCH727965) is a novel small molecule multi-CDK inhibitor with low nanomolar potency against CDK1, CDK2, CDK5 and CDK9 that has shown favorable toxicity and efficacy in preliminary mouse experiments, and has been well tolerated in Phase I clinical trials. In the current study, the therapeutic efficacy of SCH727965 on human pancreatic cancer cells was tested using in vitro and in vivo model systems. Treatment with SCH727965 significantly reduced in vitro cell growth, motility and colony formation in soft agar of MIAPaCa-2 and Pa20C cells. These phenotypic changes were accompanied by marked reduction of phosphorylation of Retinoblastoma (Rb) and reduced activation of RalA. Single agent therapy with SCH727965 (40 mg/kg i.p. twice weekly) for 4 weeks significantly reduced subcutaneous tumor growth in 10/10 (100%) of tested low-passage human pancreatic cancer xenografts. Treatment of low passage pancreatic cancer xenografts with a combination of SCH727965 and gemcitabine was significantly more effective than either agent alone. Gene Set Enrichment Analysis identified overrepresentation of the Notch and Transforming Growth Factor-β (TGF-β) signaling pathways in the xenografts least responsive to SCH727965 treatment. Treatment with the cyclin-dependent kinase inhibitor SCH727965 alone or in combination is a highly promising novel experimental therapeutic strategy against pancreatic cancer. (source: Cancer Biol Ther. 2011 Oct 1;12(7):598-609. Epub 2011 Oct 1.).

1: Gorlick R, Kolb EA, Houghton PJ, Morton CL, Neale G, Keir ST, Carol H, Lock R, Phelps D, Kang MH, Reynolds CP, Maris JM, Billups C, Smith MA. Initial testing (stage 1) of the cyclin dependent kinase inhibitor SCH 727965 (dinaciclib) by the pediatric preclinical testing program. Pediatr Blood Cancer. 2012 Feb 7. doi: 10.1002/pbc.24073. [Epub ahead of print] PubMed PMID: 22315240.

2: Feldmann G, Mishra A, Bisht S, Karikari C, Garrido-Laguna I, Rasheed Z, Ottenhof NA, Dadon T, Alvarez H, Fendrich V, Rajeshkumar NV, Matsui W, Brossart P, Hidalgo M, Bannerji R, Maitra A, Nelkin BD. Cyclin-dependent kinase inhibitor Dinaciclib (SCH727965) inhibits pancreatic cancer growth and progression in murine xenograft models. Cancer Biol Ther. 2011 Oct 1;12(7):598-609. Epub 2011 Oct 1. PubMed PMID: 21768779; PubMed Central PMCID: PMC3218385.

3: Bates DJ, Salerni BL, Lowrey CH, Eastman A. Vinblastine sensitizes leukemia cells to cyclin-dependent kinase inhibitors, inducing acute cell cycle phase-independent apoptosis. Cancer Biol Ther. 2011 Aug 15;12(4):314-25. Epub 2011 Aug 15. PubMed PMID: 21768777; PubMed Central PMCID: PMC3173732.

4: Fu W, Ma L, Chu B, Wang X, Bui MM, Gemmer J, Altiok S, Pledger WJ. The cyclin-dependent kinase inhibitor SCH 727965 (dinacliclib) induces the apoptosis of osteosarcoma cells. Mol Cancer Ther. 2011 Jun;10(6):1018-27. Epub 2011 Apr 13. PubMed PMID: 21490307.

5: Martin GE, Sunseri D. Establishing the carbon skeleton of pharmaceutical agents using HSQC-ADEQUATE spectra. J Pharm Biomed Anal. 2011 Jul 15;55(5):895-901. Epub 2011 Mar 6. PubMed PMID: 21444174.

6: Abdullah C, Wang X, Becker D. Expression analysis and molecular targeting of cyclin-dependent kinases in advanced melanoma. Cell Cycle. 2011 Mar 15;10(6):977-88. Epub 2011 Mar 15. PubMed PMID: 21358262; PubMed Central PMCID: PMC3100877.

7: Guzi TJ, Paruch K, Dwyer MP, Labroli M, Shanahan F, Davis N, Taricani L, Wiswell D, Seghezzi W, Penaflor E, Bhagwat B, Wang W, Gu D, Hsieh Y, Lee S, Liu M, Parry D. Targeting the replication checkpoint using SCH 900776, a potent and functionally selective CHK1 inhibitor identified via high content screening. Mol Cancer Ther. 2011 Apr;10(4):591-602. Epub 2011 Feb 14. PubMed PMID: 21321066.
 
8: Parry D, Guzi T, Shanahan F, Davis N, Prabhavalkar D, Wiswell D, Seghezzi W, Paruch K, Dwyer MP, Doll R, Nomeir A, Windsor W, Fischmann T, Wang Y, Oft M, Chen T, Kirschmeier P, Lees EM. Dinaciclib (SCH 727965), a novel and potent cyclin-dependent kinase inhibitor. Mol Cancer Ther. 2010 Aug;9(8):2344-53. Epub 2010 Jul 27. PubMed PMID: 20663931.