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MedKoo Cat#: 414400 | Name: Nirogacestat HBr
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Description:

WARNING: This product is for research use only, not for human or veterinary use.

Nirogacestat, also known as PF-03084014, is a potent and selective gamma secretase (GS) inhibitor with potential antitumor activity. PF-03084014 binds to GS, blocking proteolytic activation of Notch receptors. Nirogacestat enhances the Antitumor Effect of Docetaxel in Prostate Cancer. Nirogacestat enhances docetaxel-mediated tumor response and provides a rationale to explore GSIs as adjunct therapy in conjunction with docetaxel for men with CRPC (castration-resistant prostate cancer).

Chemical Structure

Nirogacestat HBr
Nirogacestat HBr
CAS#1962925-29-6 (HBr)

Theoretical Analysis

MedKoo Cat#: 414400

Name: Nirogacestat HBr

CAS#: 1962925-29-6 (HBr)

Chemical Formula: C27H43Br2F2N5O

Exact Mass: 0.0000

Molecular Weight: 651.48

Elemental Analysis: C, 49.78; H, 6.65; Br, 24.53; F, 5.83; N, 10.75; O, 2.46

Price and Availability

Size Price Availability Quantity
25mg USD 250.00 2 Weeks
50mg USD 450.00 2 Weeks
100mg USD 750.00 2 Weeks
200mg USD 1,250.00 2 Weeks
500mg USD 2,450.00 2 Weeks
1g USD 3,650.00 2 Weeks
2g USD 5,950.00 2 Weeks
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Related CAS #
1962925-29-6 (2HBr) 1290543-63-3 (free base) 2664906-78-7 (HBr) 865773-15-5 (free base) Nirogacestat mesylate
Synonym
Nirogacestat hydrobromide; Nirogacestat HBr
IUPAC/Chemical Name
(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide dihydrobromide
InChi Key
LXEYYZYDWLAIPW-KBVFCZPLSA-N
InChi Code
InChI=1S/C27H41F2N5O.2BrH/c1-7-8-23(32-20-10-9-18-11-19(28)12-22(29)21(18)13-20)25(35)33-24-14-34(17-31-24)27(5,6)16-30-15-26(2,3)4;;/h11-12,14,17,20,23,30,32H,7-10,13,15-16H2,1-6H3,(H,33,35);2*1H/t20-,23-;;/m0../s1
SMILES Code
CCC[C@H](N[C@@H]1CC2=C(C=C(F)C=C2F)CC1)C(NC3=CN(C(C)(C)CNCC(C)(C)C)C=N3)=O.[H]Br.[H]Br
Appearance
Solid powder
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
To be determined
Shelf Life
>2 years if stored properly
Drug Formulation
To be determined
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
Product Data
Product Data
Instruction
View handling instruction
Biological target:
Nirogacestat dihydrobromide (PF-3084014 dihydrobromide) is a γ-secretase inhibitor with an IC50 of 6.2 nM.
In vitro activity:
This study investigated the role of PF (PF-03084014) in the regulation of receptor activator of nuclear factor-kB ligand (RANKL)-induced osteoclastogenesis in vitro. It was found that PF could suppress the formation of osteoclasts from bone marrow macrophages (BMMs) without causing cytotoxicity, inhibit bone resorption and downregulate the mRNA level of osteoclast-specific markers, including calcitonin receptor (CTR), tartrate resistant acid phosphatase (TRAP), cathepsin K (CTSK), dendritic cell-specific transmembrane protein (Dc-stamp), Atp6v0d2 (V-ATPase d2) and nuclear factor of activated T-cells cytoplasmic 1 (NFATc1). Reference: Exp Cell Res. 2019 Sep 1;382(1):111470. https://pubmed.ncbi.nlm.nih.gov/31211955/
In vivo activity:
Guinea pigs were dosed with PF-3084014 for 5 days via osmotic minipump at 0.03 to 3 mg/kg/day and exhibited dose-dependent reduction in brain, CSF, and plasma Abeta. Brain, CSF, and plasma all exhibited dose-dependent reductions in Abeta, and the magnitude and duration of Abeta lowering exceeded those of the reductions in B-cell endpoints. Reference: J Pharmacol Exp Ther. 2010 Jul;334(1):269-77. https://pubmed.ncbi.nlm.nih.gov/20363853/
Solvent mg/mL mM comments
Solubility
DMSO 65.2 100.00
Water 6.5 10.00
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 651.48 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.

Recalculate based on batch purity %
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:
1. Chen X, Chen X, Zhou Z, Mao Y, Wang Y, Ma Z, Xu W, Qin A, Zhang S. Nirogacestat suppresses RANKL-Induced osteoclast formation in vitro and attenuates LPS-Induced bone resorption in vivo. Exp Cell Res. 2019 Sep 1;382(1):111470. doi: 10.1016/j.yexcr.2019.06.015. Epub 2019 Jun 15. PMID: 31211955. 2. Wei P, Walls M, Qiu M, Ding R, Denlinger RH, Wong A, Tsaparikos K, Jani JP, Hosea N, Sands M, Randolph S, Smeal T. Evaluation of selective gamma-secretase inhibitor PF-03084014 for its antitumor efficacy and gastrointestinal safety to guide optimal clinical trial design. Mol Cancer Ther. 2010 Jun;9(6):1618-28. doi: 10.1158/1535-7163.MCT-10-0034. Epub 2010 Jun 8. PMID: 20530712. 3. Wu CX, Xu A, Zhang CC, Olson P, Chen L, Lee TK, Cheung TT, Lo CM, Wang XQ. Notch Inhibitor PF-03084014 Inhibits Hepatocellular Carcinoma Growth and Metastasis via Suppression of Cancer Stemness due to Reduced Activation of Notch1-Stat3. Mol Cancer Ther. 2017 Aug;16(8):1531-1543. doi: 10.1158/1535-7163.MCT-17-0001. Epub 2017 May 18. PMID: 28522590. 4. Lanz TA, Wood KM, Richter KE, Nolan CE, Becker SL, Pozdnyakov N, Martin BA, Du P, Oborski CE, Wood DE, Brown TM, Finley JE, Sokolowski SA, Hicks CD, Coffman KJ, Geoghegan KF, Brodney MA, Liston D, Tate B. Pharmacodynamics and pharmacokinetics of the gamma-secretase inhibitor PF-3084014. J Pharmacol Exp Ther. 2010 Jul;334(1):269-77. doi: 10.1124/jpet.110.167379. Epub 2010 Apr 2. PMID: 20363853.
In vitro protocol:
1. Chen X, Chen X, Zhou Z, Mao Y, Wang Y, Ma Z, Xu W, Qin A, Zhang S. Nirogacestat suppresses RANKL-Induced osteoclast formation in vitro and attenuates LPS-Induced bone resorption in vivo. Exp Cell Res. 2019 Sep 1;382(1):111470. doi: 10.1016/j.yexcr.2019.06.015. Epub 2019 Jun 15. PMID: 31211955. 2. Wei P, Walls M, Qiu M, Ding R, Denlinger RH, Wong A, Tsaparikos K, Jani JP, Hosea N, Sands M, Randolph S, Smeal T. Evaluation of selective gamma-secretase inhibitor PF-03084014 for its antitumor efficacy and gastrointestinal safety to guide optimal clinical trial design. Mol Cancer Ther. 2010 Jun;9(6):1618-28. doi: 10.1158/1535-7163.MCT-10-0034. Epub 2010 Jun 8. PMID: 20530712.
In vivo protocol:
1. Wu CX, Xu A, Zhang CC, Olson P, Chen L, Lee TK, Cheung TT, Lo CM, Wang XQ. Notch Inhibitor PF-03084014 Inhibits Hepatocellular Carcinoma Growth and Metastasis via Suppression of Cancer Stemness due to Reduced Activation of Notch1-Stat3. Mol Cancer Ther. 2017 Aug;16(8):1531-1543. doi: 10.1158/1535-7163.MCT-17-0001. Epub 2017 May 18. PMID: 28522590. 2. Lanz TA, Wood KM, Richter KE, Nolan CE, Becker SL, Pozdnyakov N, Martin BA, Du P, Oborski CE, Wood DE, Brown TM, Finley JE, Sokolowski SA, Hicks CD, Coffman KJ, Geoghegan KF, Brodney MA, Liston D, Tate B. Pharmacodynamics and pharmacokinetics of the gamma-secretase inhibitor PF-3084014. J Pharmacol Exp Ther. 2010 Jul;334(1):269-77. doi: 10.1124/jpet.110.167379. Epub 2010 Apr 2. PMID: 20363853.
1: Nooka AK, Weisel K, van de Donk NW, Routledge D, Otero PR, Song K, Quach H, Callander N, Minnema MC, Trudel S, Jackson NA, Ahlers CM, Im E, Cheng S, Smith L, Hareth N, Ferron-Brady G, Brouch M, Montes de Oca R, Paul S, Holkova B, Gupta I, Kremer BE, Richardson P. Belantamab mafodotin in combination with novel agents in relapsed/refractory multiple myeloma: DREAMM-5 study design. Future Oncol. 2021 Jun;17(16):1987-2003. doi: 10.2217/fon-2020-1269. Epub 2021 Mar 8. PMID: 33682447. 2: Jia H, Wang Z, Zhang J, Feng F. γ-Secretase inhibitors for breast cancer and hepatocellular carcinoma: From mechanism to treatment. Life Sci. 2021 Mar 1;268:119007. doi: 10.1016/j.lfs.2020.119007. Epub 2021 Jan 8. PMID: 33428878. 3: Porcelli L, Mazzotta A, Garofoli M, Di Fonte R, Guida G, Guida M, Tommasi S, Azzariti A. Active notch protects MAPK activated melanoma cell lines from MEK inhibitor cobimetinib. Biomed Pharmacother. 2021 Jan;133:111006. doi: 10.1016/j.biopha.2020.111006. Epub 2020 Nov 14. PMID: 33202284. 4: López-Nieva P, González-Sánchez L, Cobos-Fernández MÁ, Córdoba R, Santos J, Fernández-Piqueras J. More Insights on the Use of γ-Secretase Inhibitors in Cancer Treatment. Oncologist. 2021 Feb;26(2):e298-e305. doi: 10.1002/onco.13595. Epub 2020 Nov 26. PMID: 33191568; PMCID: PMC7873333. 5: Paroni G, Zanetti A, Barzago MM, Kurosaki M, Guarrera L, Fratelli M, Troiani M, Ubezio P, Bolis M, Vallerga A, Biancardi F, Terao M, Garattini E. Retinoic Acid Sensitivity of Triple-Negative Breast Cancer Cells Characterized by Constitutive Activation of the notch1 Pathway: The Role of Rarβ. Cancers (Basel). 2020 Oct 18;12(10):3027. doi: 10.3390/cancers12103027. PMID: 33081033; PMCID: PMC7650753. 6: Huang D, Qiu J, Kuang S, Deng M. In Vitro Evaluation of Clinical Candidates of γ-Secretase Inhibitors: Effects on Notch Inhibition and Promoting Beige Adipogenesis and Mitochondrial Biogenesis. Pharm Res. 2020 Sep 4;37(10):185. doi: 10.1007/s11095-020-02916-7. PMID: 32888109; PMCID: PMC8011272. 7: Takahashi T, Prensner JR, Robson CD, Janeway KA, Weigel BJ. Safety and efficacy of gamma-secretase inhibitor nirogacestat (PF-03084014) in desmoid tumor: Report of four pediatric/young adult cases. Pediatr Blood Cancer. 2020 Oct;67(10):e28636. doi: 10.1002/pbc.28636. Epub 2020 Aug 6. PMID: 32762028. 8: Wang L, Zi H, Luo Y, Liu T, Zheng H, Xie C, Wang X, Huang X. Inhibition of Notch pathway enhances the anti-tumor effect of docetaxel in prostate cancer stem-like cells. Stem Cell Res Ther. 2020 Jun 26;11(1):258. doi: 10.1186/s13287-020-01773-w. PMID: 32586404; PMCID: PMC7318403. 9: Moore G, Annett S, McClements L, Robson T. Top Notch Targeting Strategies in Cancer: A Detailed Overview of Recent Insights and Current Perspectives. Cells. 2020 Jun 20;9(6):1503. doi: 10.3390/cells9061503. PMID: 32575680; PMCID: PMC7349363. 10: Katoh M, Katoh M. Precision medicine for human cancers with Notch signaling dysregulation (Review). Int J Mol Med. 2020 Feb;45(2):279-297. doi: 10.3892/ijmm.2019.4418. Epub 2019 Dec 4. PMID: 31894255; PMCID: PMC6984804. 11: Wang X, Su D, Qin Z, Chen Z. Identification of FOXN4 as a tumor suppressor of breast carcinogenesis via the activation of TP53 and deactivation of Notch signaling. Gene. 2020 Jan 5;722:144057. doi: 10.1016/j.gene.2019.144057. Epub 2019 Aug 17. Erratum in: Gene. 2021 Feb 15;769:145161. PMID: 31430519. 12: Chen X, Chen X, Zhou Z, Mao Y, Wang Y, Ma Z, Xu W, Qin A, Zhang S. Nirogacestat suppresses RANKL-Induced osteoclast formation in vitro and attenuates LPS-Induced bone resorption in vivo. Exp Cell Res. 2019 Sep 1;382(1):111470. doi: 10.1016/j.yexcr.2019.06.015. Epub 2019 Jun 15. PMID: 31211955. 13: Farah E, Li C, Cheng L, Kong Y, Lanman NA, Pascuzzi P, Lorenz GR, Zhang Y, Ahmad N, Li L, Ratliff T, Liu X. NOTCH signaling is activated in and contributes to resistance in enzalutamide-resistant prostate cancer cells. J Biol Chem. 2019 May 24;294(21):8543-8554. doi: 10.1074/jbc.RA118.006983. Epub 2019 Apr 2. PMID: 30940724; PMCID: PMC6544854. 14: Feng Y, Fu X, Lou X. Notch pathway deactivation mediated by F-box/WD repeat domain-containing 7 ameliorates hydrogen peroxide-induced apoptosis in rat periodontal ligament stem cells. Arch Oral Biol. 2019 Apr;100:93-99. doi: 10.1016/j.archoralbio.2019.02.010. Epub 2019 Feb 19. PMID: 30822705. 15: Hossain F, Sorrentino C, Ucar DA, Peng Y, Matossian M, Wyczechowska D, Crabtree J, Zabaleta J, Morello S, Del Valle L, Burow M, Collins-Burow B, Pannuti A, Minter LM, Golde TE, Osborne BA, Miele L. Notch Signaling Regulates Mitochondrial Metabolism and NF-κB Activity in Triple-Negative Breast Cancer Cells via IKKα-Dependent Non-canonical Pathways. Front Oncol. 2018 Dec 4;8:575. doi: 10.3389/fonc.2018.00575. PMID: 30564555; PMCID: PMC6289043. 16: Zheng Y, Wang Z, Xiong X, Zhong Y, Zhang W, Dong Y, Li J, Zhu Z, Zhang W, Wu H, Gu W, Wu Y, Wang X, Song X. Membrane-tethered Notch1 exhibits oncogenic property via activation of EGFR-PI3K-AKT pathway in oral squamous cell carcinoma. J Cell Physiol. 2019 May;234(5):5940-5952. doi: 10.1002/jcp.27022. Epub 2018 Dec 4. PMID: 30515785. 17: Yang X, Xia W, Chen L, Wu CX, Zhang CC, Olson P, Wang XQ. Synergistic antitumor effect of a γ-secretase inhibitor PF-03084014 and sorafenib in hepatocellular carcinoma. Oncotarget. 2018 Oct 9;9(79):34996-35007. doi: 10.18632/oncotarget.26209. PMID: 30405889; PMCID: PMC6201862. 18: Du Z, Li L, Sun W, Wang X, Zhang Y, Chen Z, Yuan M, Quan Z, Liu N, Hao Y, Li T, Wang J, Luo C, Wu X. HepaCAM inhibits the malignant behavior of castration- resistant prostate cancer cells by downregulating Notch signaling and PF-3084014 (a γ-secretase inhibitor) partly reverses the resistance of refractory prostate cancer to docetaxel and enzalutamide in vitro. Int J Oncol. 2018 Jul;53(1):99-112. doi: 10.3892/ijo.2018.4370. Epub 2018 Apr 12. PMID: 29658567; PMCID: PMC5958706. 19: Rojas JD, Lin F, Chiang YC, Chytil A, Chong DC, Bautch VL, Rathmell WK, Dayton PA. Ultrasound Molecular Imaging of VEGFR-2 in Clear-Cell Renal Cell Carcinoma Tracks Disease Response to Antiangiogenic and Notch-Inhibition Therapy. Theranostics. 2018 Jan 1;8(1):141-155. doi: 10.7150/thno.19658. PMID: 29290798; PMCID: PMC5743465. 20: Zheng Y, Wang Z, Ding X, Dong Y, Zhang W, Zhang W, Zhong Y, Gu W, Wu Y, Song X. Combined Erlotinib and PF-03084014 treatment contributes to synthetic lethality in head and neck squamous cell carcinoma. Cell Prolif. 2018 Jun;51(3):e12424. doi: 10.1111/cpr.12424. Epub 2017 Dec 12. PMID: 29232766; PMCID: PMC6528911.