Synthesis of Rucaparib, Clovis Oncology’s PARP Inh

  2014-07-15 Oncology 肿瘤Synthesis 合成

Rucaparib (AG-014699, PF-0136738), an oral inhibitor of poly (ADP-ribose polymerase 1 and 2 (PARP 1 and PARP 2), is being investigated by Clovis Oncology in several clinical studies, including the Phase II ARIEL2 study (NCT01891344), the Phase III ARIEL3 study (NCT01968213) for platinum-sensitive ovarian cancer and the Phase II RUCAPANC study for pancreatic cancer (NCT02042378).

Chemical-Structure-of-PAPP-Inhibitor-Rucaparib-Clovis Oncology’s-Investigational-Ovarian and Pancreatic cancer Drug 抗癌试验药物Rucaparib的化学结构PARP is a family of proteins involved in many functions in a cell, including DNA repair, gene expression, cell cycle control, intracellular trafficking and energy metabolism. PARP proteins play key roles in single strand break repair through the base excision repair pathway. PARP inhibitors have shown activity as a monotherapy against tumors with existing DNA repair defects, such as BRCA1 and BRCA2, and as a combination therapy when administered together with anti-cancer agents that induce DNA damage.

Chemical Structures of PARP inhibitors currently in clinical development for cancer treatment

Chemical Structure of PARP inhibitors currently in clinical development_Olaparib_Niraparib_Veliparib_Rucaparib_BMN 673_E7016

Olaparib (proposed brand name is Lynparza, Chinese Name:奥拉帕尼) is currently the leader in the field of PARP inhibitor, a drug class which is starting to live up to its early promise as a means of treating cancer by blocking the repair of DNA in tumor cells despite some early clinical setbacks including the failed phase III studies for Sanofi’s rival candidate Iniparib (BSI 201). Olaparib (奥拉帕尼) from AstraZeneca has just been turned down for accelerated approval by an FDA advisory committee, reducing its chances of winning the race. AstraZeneca will likely now have to complete an ongoing phase III trial (SOLO-2 study, NCT01874353) in ovarian cancer which is due to complete in 2015 to secure approval. Tesaro has now closed the gap in the race to bring the first PARP inhibitor to market, with its lead candidate Niraparib (previously known as MK-4827, Chinese Name: 尼拉帕尼) in a phase III trial for Her2-Negative, Germline BRCA Mutation-positive Breast Cancer due to generate data in June 2015. If positive niraparib could reach the market in early 2016. Other PARP inhibitors in clinical development include AbbVie’s Veliparib (ABT-888, Chinese Name: 维利帕尼, phase III in breast cancer and non-small cell lung cancer), BioMarin’s BMN 673 (phase III in breast cancer) and Eisai’s E7016 (phase II in melanoma).

Chemical Structures of Rociletinib (CO-1686), Clovis Oncology’s Breakthough-Designated Lung Cancer Drug 克洛维斯肿瘤公司肺癌药物Rociletinib的化学结构

Clovis Oncology’s third generation EGFR inhibitor Rociletinib (also known as CO-1686) and another similar drug, AstraZeneca’s AZD9291, are in a race to market with the first drug to treat T790M+ non-small cell lung cancer (NSCLC). Both CO-1686 and  AZD9291 were recently granted a breakthrough therapy designation by the FDA for the treatment of EGFR T790M-positive patients following progression on a prior EGFR inhibitor.

Chemical Strucure of AZD9291_EGFR Inhibitor_Non-small cell lung cancer_AstraZeneca 阿斯利康非小细胞肺癌药物AZD9291的化学结构

Clovis Oncology reported a lower response rate for CO-1686 in phase 2 trials compared to previous trials at the 2014 American Society of Clinical Oncology meeting in Chicago; the response rate fell from 64% to 58% in the patient cohort. This is below the 64% rate that was recently reported for AstraZeneca’s rival AZD9291.

Synthesis of Rucaparib Camphorsulfonate Salt, Clovis Oncology’s Investigational PARP Inhibitor for Ovarian  and Pancreatic Cancer Treatment  抗癌试验药物Rucaparib的化学合成

Synthesis of Rucaparib camphorsulfonate salt, Clovis Oncology’s Investigational PARP Inhibitor for Ovarian  and Pancreatic Cancer Treatment  抗癌试验药物Rucaparib的化学合成

Clovis公司抗癌药Rucaparib (AG-014699, PF-0136738)

生物科技公司Clovis的抗癌药物Rucaparib (AG-014699, PF-0136738))是一种新型口服的选择性聚腺苷二磷酸核糖聚合酶(PARP)抑制剂,2011年从辉瑞购入, 这款药物通过干扰细胞中DNA修复过程而起作用,这将使得肿瘤对损坏 DNA的化疗药物变得更加敏感。目前该药物正在美国进行临床试验用于卵巢癌和胰腺癌的治疗 (美国临床试验注册号NCT01891344NCT01968213NCT02042378 )。

聚腺苷二磷酸核糖聚合酶(PARP)抑制剂曾被评为抗肿瘤领域最重大的突破之一,但赛诺若菲之前的PARP抑制剂领先产品Iniparib于 2013年终止开发。2013年6月,赛诺菲公布在一个三期临床(ECLIPSE实验)中,iniparib作为增敏剂和卡培他滨或卡铂联用,并没有比单药显示更好的疗效。而且iniparib在包括耐铂卵巢癌等其它实验中也全面失利。现在PARP抑制剂处于领先地位的阿斯利康的Olaparib (奥拉帕尼) )今年6月刚刚被FDA顾问委员会拒绝加速批准,这降低了其赢得竞争的机会。阿斯利康用中期临床结果向美国FDA和欧洲EMA申报上市。2014年5月1 日,FDA授予阿斯利康的PARP抑制剂Olaparib (奥拉帕尼) 的优先审查资格。阿斯利康现在可能必须完成正在进行的卵巢癌3期临床试验,这项试验定于2015年底完成。Tesaro公司的尼拉帕尼(Niraparib)目前已越发接近将首款PARP抑制剂推向市场,尼拉帕尼(Niraparib)定于2015年获得试验数据。如果试验数据呈阳性,Niraparib有望在2016年投放市场。

正处于临床开发阶段的其它PARP抑制剂还有艾伯维研发的维利帕尼  (Veliparib, ABT-888),BioMarin的BMN 673(乳腺癌3期试验),卵巢癌2期试验)和Eisai的E7016(黑色素瘤2期试验)。


Gillmore, Adam T. et al. Multkilogram Scale-Up of a Reductive Alkylation Route to a Novel PARP Inhibitor. Organic Process Research & Development, 16(12), 1897-1904; 2012

Ma, Chunrong et a. Method of preparing azepinoindolones such as 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one, poly(adp-ribose) polymerase inhibitor. U.S. Pat. Appl. Publ., 20060063926, 23 Mar 2006

Webber, Stephen Evan et al. Preparation of 3,4-dihydropyrrolo[4,3,2-de]isoquinolin-5(1H)-ones and analogs as poly(ADP-ribose) polymerase inhibitors. PCT Int. Appl., WO2000042040, 20 Jul 200