Jul 292013
 

niraparib

  MK-4827

MK-4827 Formula: C19H20N4O 
 
MK-4827 Storage: at -20 ℃ 2 years 
MK-4827 CAS No.: 1038915-60-4

MK-4827 is an inhibitor of PARP 1 and 2 with IC50 = 3.8 and 2.1 nM, respectively, currently in clinical trials. In a whole cell assay, it inhibited PARP activity with EC50 = 4 nM and inhibited proliferation of cancer cells with mutant BRCA-1 and BRCA-2 with CC50 in the 10-100 nM range. MK-4827 was well tolerated in vivo and demonstrated efficacy as a single agent in a xenograft model of BRCA-1 deficient cancer

TESARO, Inc.  an oncology-focused biopharmaceutical company, today announced that it has initiated patient enrollment in a Phase 3 trial of niraparib, an inhibitor of poly ADP-ribose polymerase (PARP), for the treatment of ovarian cancer. This trial, referred to as NOVA, will evaluate a single daily 300 milligram dose of niraparib in 360 patients with high grade serous, platinum sensitive, relapsed ovarian cancer compared to placebo.
Read more: 

http://www.benzinga.com/news/13/07/3773861/tesaro-initiates-phase-3-trial-of-niraparib-for-treatment-of-patients-with-ovaria?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+benzinga+%28Benzinga+News+Feed%29

Biological Activity of MK-4827:
MK-4827 is a potent, selective, PARP 1/2 inhibitor with IC50 of 3.8 and 2.1 nM for PARP1 and 2, respectively. MK-4827 possesses potential antineoplastic activity. In a whole cell assay, MK-4827 prevented PARP activity with an EC50 of 4 nM, enhancing the accumulation of DNA strand breaks and promoting genomic instability and apoptosis. MK-4827 induces selective synthetic lethality in homologous recombination (HR) repair deficient tumors with BRCA1 / 2 loss and tumor cell lines with non-BRCA-related HR defects, supporting clinical utility in sporadic tumors. MK-4827 reveals good pharmacokinetic properties and is currently in phase I clin. trials. The phase I clinical trials for MK-4827 is ongoing in the treatment of solid tumors.
References on MK-4827:
1. Study of the Safety and Efficacy of MK-4827 Given With Temozolomide in Participants With Advanced Cancer (MK-4827-014 AM1).2. A Study of MK4827 in Participants With Advanced Solid Tumors or Hematologic Malignancies (MK-4827-001 AM8).

3. PARP inhibitor MK4827
Abstract 
An inhibitor of Poly (ADP-ribose) polymerase (PARP) with potential Antineoplastic Activity. PARP Inhibitor MK4827 inhibits PARP Activity, ENHANCING the accumulation of DNA Strand Breaks and promoting genomic instability and apoptosis. The PARP family of Proteins detect and repair single strand DNA breaks by the base-excision repair (BER) pathway.

4. Glendenning J, Tutt A. PARP inhibitors – Current Status and the Walk towards Early Breast cancer. Breast. 2011 Oct; 20 Suppl 3: S12-9.
Abstract 
… Early Phase Trials with efficacy endpoints have been presented for the PARP inhibitors AG014699, olaparib, veliparib, iniparib and MK4827. The results of the first phase II trials exploring monotherapy PARP inhibitor strategies, which are based on revisiting the concept of synthetic lethality, have emerged and are reviewed herein. The clinical trials that have or are exploring combinations with DNA damaging therapy in these contexts are discussed with particular reference to breast cancer, as are biomarkers that have been proposed and are being investigated to develop optimal drug schedule and patient selection criteria for these DNA repair targeting approaches.

5. Jones, Philip; Altamura, Sergio; Boueres, Julia et al. Discovery of 2 – {4 – [(3S)-Piperidin-3-yl] phenyl}-2H-INDAZOLE-7-carboxamide (MK-4827): A Novel Oral Poly (ADP-ribose) polymerase (PARP) Inhibitor efficacious in BRCA-1 and -2 Mutant Tumors. Journal of Medicinal Chemistry (2009), 52 (22), 7170-7185.
Abstract 
… We Disclose the Development of a novel series of 2-phenyl-2H-indazole-7-carboxamides as poly (ADP-ribose) polymerase (PARP) 1 and 2 inhibitors. This series was optimized to improve enzyme and cellular activity, and the resulting PARP inhibitors display antiproliferation activities against BRCA-1 and BRCA-2 deficient cancer cells, with high selectivity over BRCA proficient cells. Extrahepatic oxidation by CYP450 1A1 and 1A2 was identified as a metabolic concern, and strategies to improve pharmacokinetic properties are reported. These efforts culminated in the identification of 2 – {4 – [(3S)-piperidin-3-yl] phenyl}-2H-indazole-7-carboxamide 56 (MK-4827), which displays good pharmacokinetic properties and is currently in phase I clinical trials. This compound displays excellent PARP 1 and 2 inhibition with IC50 = 3.8 and 2.1 nM, respectively, and in a whole cell assay, it inhibited PARP activity with EC50 = 4 nM and inhibited proliferation of cancer cells with mutant BRCA-1 and BRCA-2 with CC50 in the 10? 100 nM range. Compound 56 was well tolerated in vivo and demonstrated efficacy as a single agent in a xenograft model of BRCA-1 deficient cancer.

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