Related CAS #
1262395-13-0
1262395-10-7 (recemate)
1262395-17-4 (R-isomer)
Synonym
NMS-P515; NMS-P515; NMS-P515;
IUPAC/Chemical Name
(S)-2-(1-cyclohexylpiperidin-4-yl)-1-methyl-3-oxoisoindoline-4-carboxamide
InChi Key
OYGLTKXMFGWXJT-AWEZNQCLSA-N
InChi Code
InChI=1S/C21H29N3O2/c1-14-17-8-5-9-18(20(22)25)19(17)21(26)24(14)16-10-12-23(13-11-16)15-6-3-2-4-7-15/h5,8-9,14-16H,2-4,6-7,10-13H2,1H3,(H2,22,25)/t14-/m0/s1
SMILES Code
O=C(C1=CC=CC([C@H](C)N2C3CCN(C4CCCCC4)CC3)=C1C2=O)N
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO
Shelf Life
>3 years if stored properly
Drug Formulation
This drug may be formulated in DMSO
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
More Info
Poly(ADP-ribose) polymerase-1 (PARP-1) is an enzyme involved in signaling and repair of DNA single strand breaks. PARP-1 employs NAD+ to modify substrate proteins via the attachment of poly(ADP-ribose) chains. PARP-1 is a well established target in oncology, as testified by the number of marketed drugs (e.g., Lynparza, Rubraca, Zejula, and Talzenna) used for the treatment of ovarian, breast, and prostate tumors.
Biological target:
NMS-P515 is a potent, orally active and stereospecific PARP-1 inhibitor, with a Kd of 16 nM and an IC50 of 27 nM (in Hela cells).
In vitro activity:
Similarly to (±)-13, also NMS-P515 was selective against PARP-2, -3, and TNKS-1 with a recorded KD > 10 μM on each enzyme (Table 1). The identification of NMS-P515 as a stereoselective PARP-1 inhibitor comes along with the effort in rationalizing its superior activity compared to (R)-13.
Reference: ACS Med Chem Lett. 2019 Mar 13;10(4):534-538. https://pubmed.ncbi.nlm.nih.gov/30996792/
In vivo activity:
NMS-P515 was then subjected to in vivo efficacy studies, both as monotherapy and in combination, on subcutaneously implanted Capan-1 pancreatic (BRCA2-mutated) mouse xenografts. An even more pronounced effect (maximal tumor growth inhibition, 79%; maximum body weight loss, 17%; Figure 3B), was observed when animals were treated with NMS-P515 (12 days, once a day oral dose of 80 mg/kg) in combination with Temozolomide, a DNA damaging drug (5 days starting from day 3, once a day IV dose of 62.5 mg/kg).
Reference: ACS Med Chem Lett. 2019 Mar 13;10(4):534-538. https://pubmed.ncbi.nlm.nih.gov/30996792/
Preparing Stock Solutions
The following data is based on the
product
molecular weight
355.48
Batch specific molecular weights may vary
from batch to batch
due to the degree of hydration, which will
affect the solvent
volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass |
1 mg |
5 mg |
10 mg |
| 1 mM |
1.15 mL |
5.76 mL |
11.51 mL |
| 5 mM |
0.23 mL |
1.15 mL |
2.3 mL |
| 10 mM |
0.12 mL |
0.58 mL |
1.15 mL |
| 50 mM |
0.02 mL |
0.12 mL |
0.23 mL |
Formulation protocol:
Papeo G, Orsini P, Avanzi NR, Borghi D, Casale E, Ciomei M, Cirla A, Desperati V, Donati D, Felder ER, Galvani A, Guanci M, Isacchi A, Posteri H, Rainoldi S, Riccardi-Sirtori F, Scolaro A, Montagnoli A. Discovery of Stereospecific PARP-1 Inhibitor Isoindolinone NMS-P515. ACS Med Chem Lett. 2019 Mar 13;10(4):534-538. doi: 10.1021/acsmedchemlett.8b00569. PMID: 30996792; PMCID: PMC6466814.
In vitro protocol:
Papeo G, Orsini P, Avanzi NR, Borghi D, Casale E, Ciomei M, Cirla A, Desperati V, Donati D, Felder ER, Galvani A, Guanci M, Isacchi A, Posteri H, Rainoldi S, Riccardi-Sirtori F, Scolaro A, Montagnoli A. Discovery of Stereospecific PARP-1 Inhibitor Isoindolinone NMS-P515. ACS Med Chem Lett. 2019 Mar 13;10(4):534-538. doi: 10.1021/acsmedchemlett.8b00569. PMID: 30996792; PMCID: PMC6466814.
In vivo protocol:
Papeo G, Orsini P, Avanzi NR, Borghi D, Casale E, Ciomei M, Cirla A, Desperati V, Donati D, Felder ER, Galvani A, Guanci M, Isacchi A, Posteri H, Rainoldi S, Riccardi-Sirtori F, Scolaro A, Montagnoli A. Discovery of Stereospecific PARP-1 Inhibitor Isoindolinone NMS-P515. ACS Med Chem Lett. 2019 Mar 13;10(4):534-538. doi: 10.1021/acsmedchemlett.8b00569. PMID: 30996792; PMCID: PMC6466814.
Discovery of Stereospecific PARP-1 Inhibitor Isoindolinone NMS-P515
Gianluca Papeo, Paolo Orsini, Nilla R. Avanzi, Daniela Borghi, Elena Casale, Marina Ciomei, Alessandra Cirla, Viviana Desperati, Daniele Donati, Eduard R. Felder, Arturo Galvani, Marco Guanci, Antonella Isacchi, Helena Posteri, Sonia Rainoldi, Federico Riccardi-Sirtori, Alessandra Scolaro, and Alessia Montagnoli
Publication Date (Web): March 13, 2019 (Letter)
DOI: 10.1021/acsmedchemlett.8b00569
