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Ribociclib, рибоциклиб , ريبوسيكليب , 瑞波西利
Ribociclib (LEE 011)
Chemical Formula: C23H30N8O
Exact Mass: 434.25426
7-Cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide
Current developer: Novartis /Astex Pharmaceuticals.
Novartis Ag, Astex Therapeutics Ltd.
Ribociclib (LEE011) is an orally available, and highly specific CDK4/6 inhibitor. Phase 3.
CDK4 AND 6
(Cell-free assay)Product Ingredients
NOW FDA APPROVED 2017 since the blog post was written
|Kisqali||FDA 3/13/2017||To treat postmenopausal women with a type of advanced breast cancer
Drug Trials Snapshot
Ribociclib is in phase III clinical trials by Novatis for the treatment of postmenopausal women with advanced breast cancer.
Phase II clinical trials are also in development for the treatment of liposarcoma, ovarian cancer, fallopian tube cancer, peritoneum cancer, endometrial cancer, and gastrointestinal cancer.
Ribociclib, also known as LEE011, is an orally available cyclin-dependent kinase (CDK) inhibitor targeting cyclin D1/CDK4 and cyclin D3/CDK6 cell cycle pathway, with potential antineoplastic activity. CDK4/6 inhibitor LEE011 specifically inhibits CDK4 and 6, thereby inhibiting retinoblastoma (Rb) protein phosphorylation. Inhibition of Rb phosphorylation prevents CDK-mediated G1-S phase transition, thereby arresting the cell cycle in the G1 phase, suppressing DNA synthesis and inhibiting cancer cell growth. Overexpression of CDK4/6, as seen in certain types of cancer, causes cell cycle deregulation
Orally bioavailable CDK4/6-selective inhibitor that has been tested in Phase III clinical trials for treatment of advanced breast cancer.
CDK full name of cyclin-dependent kinases, there are many other subtypes CDK1-11, capable of binding to cell cycle proteins regulate the cell cycle. Pfizer Palbociclib been submitted for FDA review under phase II clinical data, Novartis Ribociclib (LEE011), Lilly Abemaciclib (LY2835219) the three CDK4 / 6 inhibitors have entered late stage development for the treatment of breast cancer
7-Cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide
Following Buchwald Method B, then General Procedure A, 2-chloro-7-cyclopentyl-7H- pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (300 mg, 1.02 mmol) and 5-piperazin-1- yl-pyridin-2-ylamine (314 mg, 1.13 mmol) gave 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2- ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (142 mg, 36%). MS(ESI) m/z 435.3 (M+H)+
TAKEN FROM ….http://www.joygooo.com/news_71.htm?pageNum=21
PCT Int Appl, WO2012061156.
US Pat Appl Publ, US20120115878
PCT Int Appl, WO2011130232 5) Brain, Christopher Thomas et al; Preparation of pyrrolopyrimidine Derivatives for Use as CDK4 / 6 inhibitors;. PCT Int Appl, WO2011101409.
PCT Int Appl, WO2011101417. 7) Besong, Gilbert et al;.
PCT Int Appl, WO2010020675.
PCT Int Appl, WO2007140222.
Reference：1. WO2012064805A1 / US20120115878A1.
2. WO2010020675A1 / US8415355B2.
3. WO2011130232A1 / US20130035336A1.
Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2015-10-17)
|NCT02571829||Not yet recruiting||Liposarcoma|Soft Tissue Sarcoma||Hadassah Medical Organization||December 2015||Phase 2|
|NCT02524119||Not yet recruiting||Hepatocellular Carcinoma||University of Texas Southwestern Medical Center|Novartis …more||November 2015||Phase 2|
|NCT02494921||Recruiting||Prostate Cancer||Rahul Aggarwal|University of California, San Francisco||September 2015||Phase 1|Phase 2|
|NCT02420691||Recruiting||Gastrointestinal Cancer||M.D. Anderson Cancer Center|Novartis||August 2015||Phase 2|
|NCT02431481||Not yet recruiting||Normal Renal Function|Impaired Renal Function||Novartis Pharmaceuticals|Novartis||August 2015||Phase 1|
Protocols from literature
In vitro protocol::
Pharmacologic growth inhibition: Clin Cancer Res. 2013 Nov 15;19(22):6173-82.
Cell-cycle analysis: Clin Cancer Res. 2013 Nov 15;19(22):6173-82.
Senescence and apoptosis assays: Clin Cancer Res. 2013 Nov 15;19(22):6173-82.
In vivo protocol:
Xenograft therapeutic trials: Clin Cancer Res. 2013 Nov 15;19(22):6173-82
Immunohistochemistry of xenografted neuroblastomas.Clin Cancer Res. 2013 Nov 15;19(22):6173-82
Ribociclib (LEE011) is a Me-Too version of palbociclib. Their structures are compared side-by-side as the following:
Ribociclib (LEE011) is currently being developed by Novartis and Astex. According its Novartis’s website, LEE011 is a novel, orally available, selective inhibitor of CDK4/6 kinases, which induces complete dephosphorylation of Rb and G1 arrest in cancer cells. In preclinical in vitro and in vivo tumor models, LEE011 has been shown active in cancers harboring aberrations that increase CDK4/6 activity, including those directly linked to the kinases as well as activating alterations in the upstream regulators. First-in-human study of LEE011 in patients with solid tumors and lymphoma is currently ongoing. (source: http://www.novartisoncology.us/research/pipeline/lee011.jsp).
Treatment with LEE011 significantly reduced proliferation in 12 of 17 human neuroblastoma-derived cell lines by inducing cytostasis at nanomolar concentrations (mean IC50 = 307 ± 68 nmol/L in sensitive lines). LEE011 caused cell-cycle arrest and cellular senescence that was attributed to dose-dependent decreases in phosphorylated RB and FOXM1, respectively. In addition, responsiveness of neuroblastoma xenografts to LEE011 translated to the in vivo setting in that there was a direct correlation of in vitro IC50 values with degree of subcutaneous xenograft growth delay. Although our data indicate that neuroblastomas sensitive to LEE011 were more likely to contain genomic amplification of MYCN (P = 0.01), the identification of additional clinically accessible biomarkers is of high importance. LEE011 is active in a large subset of neuroblastoma cell line and xenograft models, and supports the clinical development of this CDK4/6 inhibitor as a therapy for patients with this disease. (Clin Cancer Res. 2013 Nov 15;19(22):6173-82)
1. Rader J, Russell MR, Hart LS, Nakazawa MS, Belcastro LT, Martinez D, Li Y, Carpenter EL, Attiyeh EF, Diskin SJ, Kim S, Parasuraman S, Caponigro G, Schnepp RW, Wood AC, Pawel B, Cole KA, Maris JM. Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma. Clin Cancer Res. 2013 Nov 15;19(22):6173-82. doi: 10.1158/1078-0432.CCR-13-1675. Epub 2013 Sep 17. PubMed PMID: 24045179; PubMed Central PMCID: PMC3844928.
2. Caponigro, Giordano; Stuart, Darrin; Kim, Sunkyu; Loo, Alice; Delach, Scott. Pharmaceutical combinations of a CDK4/6 inhibitor and a B-RAF inhibitor for treatment of proliferative diseases such as cancer. PCT Int. Appl. (2014), WO 2014018725 A1 20140130.
3. Kim, Sunkyu; Doshi, Shivang; Haas, Kristy; Kovats, Steven; Huang, Alan Xizhong; Chen, Yan. Combination therapy comprising a cyclin dependent kinase 4/6 (CDK4/6) inhibitor and a phosphatidylinositol 3-kinase (PI3K) inhibitor for use in the treatment of cancer. PCT Int. Appl. (2013), WO 2013006532 A1 20130110
4. Kim, Sunkyu; Doshi, Shivang; Haas, Kristy; Kovats, Steven. Combination of cyclin dependent kinase 4/6 (CDK4/6) inhibitor and fibroblast growth factor receptor (FGFR) kinase inhibitor for the treatment of cancer. PCT Int. Appl. (2013), WO 2013006368 A1 20130110
5. Calienni, John Vincent; Chen, Guang-Pei; Gong, Baoqing; Kapa, Prasad Koteswara; Saxena, Vishal. Salt(s) of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide and processes of making thereof. U.S. Pat. Appl. Publ. (2012), US 20120115878 A1 20120510.
6. Borland, Maria; Brain, Christopher Thomas; Doshi, Shivang; Kim, Sunkyu; Ma, Jianguo; Murtie, Josh; Zhang, Hong. Combination comprising a cyclin dependent kinase 4 or cyclin dependent kinase (cdk4/6) inhibitor and an Mtor inhibitor for treating cancer. PCT Int. Appl. (2011), WO 2011130232 A1 20111020
7. Besong, Gilbert; Brain, Christopher Thomas; Brooks, Clinton A.; Congreve, Miles Stuart; Dagostin, Claudio; He, Guo; Hou, Ying; Howard, Steven; Li, Yue; Lu, Yipin; et al. Preparation of pyrrolopyrimidine compounds as CDK inhibitors. PCT Int. Appl. (2010), WO 2010020675 A1 20100225.
Cyclin-dependent kinase inhibitors (14 compounds) under clinical evaluation.
LEE-011 is one of the most selective inhibitors for CDK4 and CDK6  and is being developed by Astex Pharmaceuticals™ and Novartis. In January 2014 this inhibitor entered phase III clinical trials for the treatment of breast cancer . Due to encouraging results LEE-011 has now become the main competing drug-candidate with Pfizer’s PD0332991 (palbociclib), see Figure 3 .
Upon comparison of the chemical structure of Novartis’ LEE-011 and Pfizer’s PD0332991, the similarity is evident. The major difference lies in the bicyclic core since LEE-011 possesses a pyrrolo-pyrimidine and PD0332991 a pyridopyrimidine. The “east” part of the structure is also modified. The structural similarities make their analogous CDKs inhibition profiles (high selectivity for CDK4 and CDK6) quite obvious Moreover, both derivatives are orally administered which is pretty advantageous compared with dinaciclib, which is also in phase III clinical trials but is administered intravenously.
- Kurt, S. LEE011 CDK Inhibitor Showing Early Promise in Drug-Resistant Cancers. Oncol. Times 2014, 36, 39–40. [Google Scholar]
- Macmillan Publishers Limited. CDK inhibitors speed ahead. Nat. Rev. Drug Discov. 2014, 13, 323. [Google Scholar] [CrossRef]
1)Rader, JulieAnn et al.;Dual CDK4/CDK6 Inhibition Induces Cell-Cycle Arrest and Senescence in Neuroblastoma;Clinical Cancer Research (2013), 19(22), 6173-6182
2)Tavares, Francis X. and Strum, Jay C.;Preparation of pyrazinopyrrolopyrimidine derivatives and analogs for use as CDK inhibitors;PCT Int. Appl., WO2012061156
3)Calienni, John Vincent et al.;Salt(s) of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide and processes of making thereof;U.S. Pat. Appl. Publ., US20120115878
4)Borland, Maria et al;Combination comprising a cyclin dependent kinase 4 or cyclin dependent kinase (cdk4/6) inhibitor and an Mtor inhibitor for treating cancer;PCT Int. Appl., WO2011130232
5)Brain, Christopher Thomas et al;Preparation of pyrrolopyrimidine derivatives for use as CDK4/6 inhibitors;PCT Int. Appl., WO2011101409
6)Brain, Christopher Thomas and Perez, Lawrence Blas; Preparation of deuterated pyrrolopyrimidine compounds as inhibitors of CDK4/6 for treating cancer; PCT Int. Appl., WO2011101417
7)Besong, Gilbert et al.;Preparation of pyrrolopyrimidine compounds as CDK inhibitors;PCT Int. Appl., WO2010020675
8)Brain, Christopher Thomas et al.;Preparation of pyrrolopyrimidine compounds as protein kinase inhibitors; PCT Int. Appl., WO2007140222
9)A Randomized Double-blind, Placebo-controlled Study of LEE011 in Combination With Letrozole for the Treatment of Postmenopausal Women With Hormone Receptor Positive, HER2 Negative, Advanced Breast Cancer Who Received no Prior Therapy for Advanced Disease;ClinicalTrials.gov Identifier: NCT01958021
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