Nirogacestat free base
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MedKoo CAT#: 525757

CAS#: 1290543-63-3 (free base)

Description: 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

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Nirogacestat free base
CAS# 1290543-63-3 (free base)

Theoretical Analysis

MedKoo Cat#: 525757
Name: Nirogacestat free base
CAS#: 1290543-63-3 (free base)
Chemical Formula: C27H41F2N5O
Exact Mass: 489.33
Molecular Weight: 489.656
Elemental Analysis: C, 66.23; H, 8.44; F, 7.76; N, 14.30; O, 3.27

Price and Availability

Size Price Availability Quantity
100mg USD 2450 2 Weeks
200mg USD 4450 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: PF-03084014; PF03084014; PF 03084014; PF-3084014; PF3084014; PF 3084014; Nirogacestat

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

InChi Key: VFCRKLWBYMDAED-REWPJTCUSA-N

InChi Code: InChI=1S/C27H41F2N5O/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)/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

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: Soluble in DMSO, not in water

Shelf Life: >2 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: Notch signaling pathway inhibition may follow, which may result in the induction of apoptosis in tumor cells that overexpress Notch. The integral membrane protein GS is a multi-subunit protease complex that cleaves single-pass transmembrane proteins, such as Notch receptors, at residues within their transmembrane domains. Overexpression of the Notch signaling pathway has been correlated with increased tumor cell growth and survival.

Product Data:
Biological target: PF-03084014 inhibits the Notch signalling pathway.
In vitro activity: In this study, the role of PF in the regulation of receptor activator of nuclear factor-kB ligand (RANKL)-induced osteoclastogenesis was investigated in vitro, and the lipopolysaccharide (LPS)-induced bone resorption in vivo. 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). Furthermore, Notch2 signaling, as well as RANKL-induced AKT signaling was significantly inhibited in BMMs. Consistent with in vitro observation, we found that PF greatly ameliorated LPS-induced bone resorption. Taken together, this study demonstrated that PF has a great potential to be used in management of osteolytic diseases. Refernce: 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.
In vivo activity: In this study, the role of PF in the regulation of receptor activator of nuclear factor-kB ligand (RANKL)-induced osteoclastogenesis was investigated in vitro, and the lipopolysaccharide (LPS)-induced bone resorption in vivo. 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). Furthermore, Notch2 signaling, as well as RANKL-induced AKT signaling was significantly inhibited in BMMs. Consistent with in vitro observation, we found that PF greatly ameliorated LPS-induced bone resorption. Taken together, this study demonstrated that PF has a great potential to be used in management of osteolytic diseases. Refernce: 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. objective response rate after therapy with the γ-secretase inhibitor PF-03084014 was evaluated in patients with recurrent, refractory, progressive desmoid tumors. Patients and Methods Seventeen patients with desmoid tumors received PF-03084014 150 mg orally twice a day in 3-week cycles. Response to treatment was evaluated at cycle 1 and every six cycles, that is, 18 weeks, by RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1. Patient-reported outcomes were measured at baseline and at every restaging visit by using the MD Anderson Symptoms Inventory. Archival tumor and blood samples were genotyped for somatic and germline mutations in APC and CTNNB1. Results Of 17 patients accrued to the study, 15 had mutations in APC or CTNNB1 genes. Sixteen patients (94%) were evaluable for response; five (29%) experienced a confirmed partial response and have been on study for more than 2 years. Another five patients with prolonged stable disease as their best response remain on study. Patient-reported outcomes confirmed clinician reporting that the investigational agent was well tolerated and, in subgroup analyses, participants who demonstrated partial response also experienced clinically meaningful and statistically significant improvements in symptom burden. Conclusion PF-03084014 was well tolerated and demonstrated promising clinical benefit in patients with refractory, progressive desmoid tumors who receive long-term treatment. Refrence: Kummar S, O'Sullivan Coyne G, Do KT, Turkbey B, Meltzer PS, Polley E, Choyke PL, Meehan R, Vilimas R, Horneffer Y, Juwara L, Lih A, Choudhary A, Mitchell SA, Helman LJ, Doroshow JH, Chen AP. Clinical Activity of the γ-Secretase Inhibitor PF-03084014 in Adults With Desmoid Tumors (Aggressive Fibromatosis). J Clin Oncol. 2017 May 10;35(14):1561-1569. doi: 10.1200/JCO.2016.71.1994. Epub 2017 Mar 28. PMID: 28350521; PMCID: PMC5455706.

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
Water 1.0 2.04

Preparing Stock Solutions

The following data is based on the product molecular weight 489.66 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: 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.
In vitro protocol: 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.
In vivo 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 Kummar S, O'Sullivan Coyne G, Do KT, Turkbey B, Meltzer PS, Polley E, Choyke PL, Meehan R, Vilimas R, Horneffer Y, Juwara L, Lih A, Choudhary A, Mitchell SA, Helman LJ, Doroshow JH, Chen AP. Clinical Activity of the γ-Secretase Inhibitor PF-03084014 in Adults With Desmoid Tumors (Aggressive Fibromatosis). J Clin Oncol. 2017 May 10;35(14):1561-1569. doi: 10.1200/JCO.2016.71.1994. Epub 2017 Mar 28. PMID: 28350521; PMCID: PMC5455706.

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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.