The DOI matches its Crossref record; 37 of the 37 references it cites were found in a registry or an index.
Discovery of 2-{4-[(3 S)-Piperidin-3-yl]phenyl}-2 H-indazole-7-carboxamide (MK-4827): A Novel Oral Poly(ADP-ribose)polymerase (PARP) Inhibitor Efficacious in BRCA-1 and -2 Mutant Tumors
Open accessAbstract
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 IC(50) = 3.8 and 2.1 nM, respectively, and in a whole cell assay, it inhibited PARP activity with EC(50) = 4 nM and inhibited proliferation of cancer cells with mutant BRCA-1 and BRCA-2 with CC(50) 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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Cites
Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy
Farmer, H., McCabe, N., Lord, C. J., Tutt, A. N. J., Johnson, D. A., Richardson, T. B., Santarosa, M., Dillon, K. J., Hickson, I., Knights, C., et al. (2005) · Nature · doi:10.1038/nature03445 · Cited by 6,683
Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase
Bryant, H. E., Schultz, N., Thomas, H. D., Parker, K. M., Flower, D., Lopez, E., Kyle, S., Meuth, M., Curtin, N. J., & Helleday, T. (2005) · Nature · doi:10.1038/nature03443 · Cited by 5,198
Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from BRCA Mutation Carriers
Fong, P. C., Boss, D. S., Yap, T. A., Tutt, A., Wu, P., Mergui-Roelvink, M., Mortimer, P., Swaisland, H., Lau, A., O'Connor, M. J., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0900212 · Cited by 3,634
Poly(ADP-ribose): novel functions for an old molecule
Schreiber, V., Dantzer, F., Ame, J.-C., & de Murcia, G. (2006) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1963 · Cited by 1,915
Cancer Susceptibility and the Functions of BRCA1 and BRCA2
Venkitaraman, A. R. (2002) · Cell · doi:10.1016/s0092-8674(02)00615-3 · Cited by 1,713
Martignoni, M., Groothuis, G. M. M., & de Kanter, R. (2006) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425255.2.6.875 · Cited by 1,478
Amé, J., Spenlehauer, C., & de Murcia, G. (2004) · BioEssays · doi:10.1002/bies.20085 · Cited by 1,459
McCabe, N., Turner, N. C., Lord, C. J., Kluzek, K., Białkowska, A., Swift, S., Giavara, S., O'Connor, M. J., Tutt, A. N., Zdzienicka, M. Z., et al. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-0140 · Cited by 1,310
(ADP-ribose)n participates in DNA excision repair
Durkacz, B. W., Omidiji, O., Gray, D. A., & Shall, S. (1980) · Nature · doi:10.1038/283593a0 · Cited by 1,121
Requirement of poly(ADP-ribose) polymerase in recovery from DNA damage in mice and in cells
de Murcia, J. M., Niedergang, C., Trucco, C., Ricoul, M., Dutrillaux, B., Mark, M., Oliver, F. J., Masson, M., Dierich, A., LeMeur, M., et al. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.14.7303 · Cited by 1,056
Cited by
Lehmann, B. D., Bauer, J. A., Chen, X., Sanders, M. E., Chakravarthy, A. B., Shyr, Y., & Pietenpol, J. A. (2011) · Journal of Clinical Investigation · doi:10.1172/jci45014 · Cited by 5,592
PARP inhibition: PARP1 and beyond
Rouleau, M., Patel, A., Hendzel, M. J., Kaufmann, S. H., & Poirier, G. G. (2010) · Nature Reviews Cancer · doi:10.1038/nrc2812 · Cited by 1,298
State-of-the-art strategies for targeting the DNA damage response in cancer
Pilié, P. G., Tang, C., Mills, G. B., & Yap, T. A. (2019) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-018-0114-z · Cited by 1,189
PARP and PARG inhibitors in cancer treatment
Slade, D. (2020) · Genes & Development · doi:10.1101/gad.334516.119 · Cited by 667
Pirinen, E., Cantó, C., Jo, Y. S., Morato, L., Zhang, H., Menzies, K. J., Williams, E. G., Mouchiroud, L., Moullan, N., Hagberg, C., et al. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.04.002 · Cited by 254
“MRL-45696, kindly provided by Thomas Vogt from Merck Research Laboratories, is closely related to the potent Parib, niraparib, or 2-phenyl-2H-indazole-7-carboxamide (Jones et al., 2009).”
Background
Metadata
- Authors
- Jones, P., Altamura, S., Boueres, J., Ferrigno, F., Fonsi, M., Giomini, C., Lamartina, S., Monteagudo, E., Ontoria, J. M., Orsale, M. V., Palumbi, M. C., Pesci, S., Roscilli, G., Scarpelli, R., Schultz-Fademrecht, C., Toniatti, C., & Rowley, M.
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2009-10-29
- Volume
- 52
- Issue
- 22
- Pages
- 7170-7185
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2160399783
- Cited by
- 316
- References
- 37
- FWCI
- 5.22
- Type
- journal article
- Language
- en
- Open access
- green
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- CoChat. (2026). Citation check: Discovery of 2-{4-[(3 S)-Piperidin-3-yl]phenyl}-2 H-indazole-7-carboxamide (MK-4827): A Novel Oral Poly(ADP-ribose)polymerase (PARP) Inhibitor Efficacious in BRCA-1 and -2 Mutant Tumors. https://app.cochat.ai/papers/10.1021/jm901188v
- The paper
- Jones, P., Altamura, S., Boueres, J., Ferrigno, F., Fonsi, M., Giomini, C., Lamartina, S., Monteagudo, E., Ontoria, J. M., Orsale, M. V., Palumbi, M. C., Pesci, S., Roscilli, G., Scarpelli, R., Schultz-Fademrecht, C., Toniatti, C., & Rowley, M. (2009). Discovery of 2-{4-[(3 S)-Piperidin-3-yl]phenyl}-2 H-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. https://doi.org/10.1021/jm901188v
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