LY3039478 | Crenigacestat | CAS#1421438-81-4 | Notch Inhibitor

MedKoo Cat#: 206102 | Name: Crenigacestat

Description:

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

Crenigacestat, also known as LY3039478, is a orally bioavailable, novel small molecule Notch inhibitor with an IC50 of ~1nM in most of the tumor cell lines tested. LY3039478 potently inhibits mutant Notch receptor activity. In a xenograft tumor model, LY3039478 inhibited N1ICD cleavage and expression of Notch-regulated genes in the tumor microenvironment. LY3039478 is being investigated in Phase I.

Chemical Structure

Crenigacestat

CAS#1421438-81-4 (free base)

Theoretical Analysis

MedKoo Cat#: 206102

Name: Crenigacestat

CAS#: 1421438-81-4 (free base)

Chemical Formula: C22H23F3N4O4

Exact Mass: 464.1671

Molecular Weight: 464.44

Elemental Analysis: C, 56.89; H, 4.99; F, 12.27; N, 12.06; O, 13.78

Price and Availability

Size	Price	Availability
5mg	USD 150.00	Ready to ship
10mg	USD 250.00	Ready to ship
25mg	USD 450.00	Ready to ship
50mg	USD 750.00	Ready to ship
100mg	USD 1,250.00	Ready to ship
200mg	USD 2,250.00	Ready to ship

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Related CAS #

1421438-81-4 (free base) 1421439-98-6 (H2O)

Synonym

LY3039478; LY 3039478; LY-3039478; Crenigacestat

IUPAC/Chemical Name

4,4,4-trifluoro-N-((S)-1-(((S)-5-(2-hydroxyethyl)-6-oxo-6,7-dihydro-5H-benzo[d]pyrido[2,3-b]azepin-7-yl)amino)-1-oxopropan-2-yl)butanamide

InChi Key

YCBAQKQAINQRFW-UGSOOPFHSA-N

InChi Code

InChI=1S/C22H23F3N4O4/c1-13(27-17(31)8-9-22(23,24)25)20(32)28-18-15-6-3-2-5-14(15)16-7-4-10-26-19(16)29(11-12-30)21(18)33/h2-7,10,13,18,30H,8-9,11-12H2,1H3,(H,27,31)(H,28,32)/t13-,18-/m0/s1

SMILES Code

O=C(N[C@@H](C)C(N[C@H]1C2=CC=CC=C2C3=CC=CN=C3N(CCO)C1=O)=O)CCC(F)(F)F

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

LY3039478 is a Notch Inhibitor with potential anticancer activity. Notch signaling plays an important role during development and tissue homeostasis. Dysregulation of Notch signaling due to mutation or amplification, or overexpression of ligands and/or receptors is implicated in a number of malignancies. Therefore, inhibition of Notch signaling is a potential target for the development of cancer therapeutics

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#S9S11C14

QC Data

View QC data: current batch, Lot#S9S11C14

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

Crenigacestat (LY3039478) is a Notch γ-secretase inhibitor, with an IC50 of 1 nM in most of the tumor cell lines tested.

In vitro activity:

The effects of Notch pathway suppression by the Crenigacestat (LY3039478)-specific inhibitor were evaluated in human iCCA cell lines and the PDX model. In vitro, LY3039478 significantly reduced Notch pathway components, including NICD1 and HES1, but not the other Notch receptors, in a panel of five different iCCA cell lines. In the PDX model, LY3039478 significantly inhibited the Notch pathway and tumor growth to the same extent as gemcitabine. Furthermore, gene expression analysis of iCCA mouse tissues treated with LY3039478 revealed a downregulation of VEGFA, HES1, and MMP13 genes. In an in vitro angiogenesis model, LY3039478 inhibited vessel formation, which was restored by the addition of MMP13. Finally, RNA-sequencing expression data of iCCA patients and matched surrounding normal liver tissues downloaded from the GEO database demonstrated that NOTCH1, HES1, MMP13, DLL4, and VEGFA genes were significantly upregulated in tumors compared with adjacent nontumorous tissues. Cell Death Differ. 2020 Aug; 27(8): 2330–2343. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370218/

In vivo activity:

Based on IPA prediction, it was hypothesized that LY3039478 inhibits iCCA tumor progression by hampering angiogenesis. To test the hypothesis, the effectiveness of LY3039478 on angiogenesis was tested in vivo. Specifically, VEGFA, DLL4, and CD31 levels were significantly (P < 0.05) downregulated as measured by western blotting (Fig. 6a). Also, VEGFA colocalizes with CD31, and both expression as well as that of DLL4 was inhibited in the iCCA tissues from animals treated as compared with those untreated (Fig. 6b and Supplementary Figs. 6, 7). In addition, MMP13 immunolocalized by immunofluorescence was downregulated in treated versus untreated mice (Fig. 6c and Supplementary Figs. 8, 9). These results suggest that the treatment of LY3039478 induces the inhibition of the DLL4/Notch signaling, producing a deregulation of VEGFA, CD31, MMP13, and tumor vascularization. Cell Death Differ. 2020 Aug; 27(8): 2330–2343. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370218/

	Solvent	mg/mL	mM
Solubility
	DMSO	30.0	64.59

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 464.44 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:

1. Mancarella S, Serino G, Dituri F, Cigliano A, Ribback S, Wang J, Chen X, Calvisi DF, Giannelli G. Crenigacestat, a selective NOTCH1 inhibitor, reduces intrahepatic cholangiocarcinoma progression by blocking VEGFA/DLL4/MMP13 axis. Cell Death Differ. 2020 Aug;27(8):2330-2343. doi: 10.1038/s41418-020-0505-4. Epub 2020 Feb 10. PMID: 32042099; PMCID: PMC7370218. 2. Wang YL, Zhang Y, Huang XY, Zheng Y. Reversing effect of NOTCH1 inhibitor LY3039478 on drug-resistance cells SGC7901/DDP of human gastric cancer and its mechanism. Eur Rev Med Pharmacol Sci. 2018 Jul;22(13):4121-4127. doi: 10.26355/eurrev_201807_15404. PMID: 30024600. 3.Mancarella S, Serino G, Dituri F, Cigliano A, Ribback S, Wang J, Chen X, Calvisi DF, Giannelli G. Crenigacestat, a selective NOTCH1 inhibitor, reduces intrahepatic cholangiocarcinoma progression by blocking VEGFA/DLL4/MMP13 axis. Cell Death Differ. 2020 Aug;27(8):2330-2343. doi: 10.1038/s41418-020-0505-4. Epub 2020 Feb 10. PMID: 32042099; PMCID: PMC7370218.

In vitro protocol:

In vivo protocol:

1: Mancarella S, Gigante I, Serino G, Pizzuto E, Dituri F, Valentini MF, Wang J, Chen X, Armentano R, Calvisi DF, Giannelli G. Crenigacestat blocking notch pathway reduces liver fibrosis in the surrounding ecosystem of intrahepatic CCA viaTGF-β inhibition. J Exp Clin Cancer Res. 2022 Nov 28;41(1):331. doi: 10.1186/s13046-022-02536-6. PMID: 36443822; PMCID: PMC9703776. 2: Lobov AA, Boyarskaya NV, Kachanova OS, Gromova ES, Shishkova AA, Zainullina BR, Pishchugin AS, Filippov AA, Uspensky VE, Malashicheva AB. Crenigacestat (LY3039478) inhibits osteogenic differentiation of human valve interstitial cells from patients with aortic valve calcification in vitro. Front Cardiovasc Med. 2022 Sep 29;9:969096. doi: 10.3389/fcvm.2022.969096. PMID: 36247471; PMCID: PMC9556293. 3: Mancarella S, Serino G, Dituri F, Cigliano A, Ribback S, Wang J, Chen X, Calvisi DF, Giannelli G. Crenigacestat, a selective NOTCH1 inhibitor, reduces intrahepatic cholangiocarcinoma progression by blocking VEGFA/DLL4/MMP13 axis. Cell Death Differ. 2020 Aug;27(8):2330-2343. doi: 10.1038/s41418-020-0505-4. Epub 2020 Feb 10. PMID: 32042099; PMCID: PMC7370218. 4: Massard C, Cassier PA, Azaro A, Anderson B, Yuen E, Yu D, Oakley G 3rd, Benhadji KA, Pant S. A phase 1b study of crenigacestat (LY3039478) in combination with gemcitabine and cisplatin or gemcitabine and carboplatin in patients with advanced or metastatic solid tumors. Cancer Chemother Pharmacol. 2022 Oct;90(4):335-344. doi: 10.1007/s00280-022-04461-z. Epub 2022 Aug 28. PMID: 36030462. 5: Mancarella S, Serino G, Gigante I, Cigliano A, Ribback S, Sanese P, Grossi V, Simone C, Armentano R, Evert M, Calvisi DF, Giannelli G. CD90 is regulated by notch1 and hallmarks a more aggressive intrahepatic cholangiocarcinoma phenotype. J Exp Clin Cancer Res. 2022 Feb 16;41(1):65. doi: 10.1186/s13046-022-02283-8. Erratum in: J Exp Clin Cancer Res. 2023 Apr 18;42(1):88. PMID: 35172861; PMCID: PMC8851853. 6: Doi T, Tajimi M, Mori J, Asou H, Inoue K, Benhadji KA, Naito Y. A phase 1 study of crenigacestat (LY3039478), the Notch inhibitor, in Japanese patients with advanced solid tumors. Invest New Drugs. 2021 Apr;39(2):469-476. doi: 10.1007/s10637-020-01001-5. Epub 2020 Sep 16. PMID: 32939607; PMCID: PMC7960611. 7: Borthakur G, Martinelli G, Raffoux E, Chevallier P, Chromik J, Lithio A, Smith CL, Yuen E, Oakley GJ 3rd, Benhadji KA, DeAngelo DJ. Phase 1 study to evaluate Crenigacestat (LY3039478) in combination with dexamethasone in patients with T-cell acute lymphoblastic leukemia and lymphoma. Cancer. 2021 Feb 1;127(3):372-380. doi: 10.1002/cncr.33188. Epub 2020 Oct 27. PMID: 33107983. 8: Pont MJ, Hill T, Cole GO, Abbott JJ, Kelliher J, Salter AI, Hudecek M, Comstock ML, Rajan A, Patel BKR, Voutsinas JM, Wu Q, Liu L, Cowan AJ, Wood BL, Green DJ, Riddell SR. γ-Secretase inhibition increases efficacy of BCMA-specific chimeric antigen receptor T cells in multiple myeloma. Blood. 2019 Nov 7;134(19):1585-1597. doi: 10.1182/blood.2019000050. PMID: 31558469; PMCID: PMC6871311. 9: Mir O, Watson S, Massard C, Le Cesne A, Benhadji KA, Soria JC. Sequential treatment with NOTCH inhibitor crenigacestat followed by pazopanib in soft tissue sarcoma patients. Ann Oncol. 2020 Dec;31(12):1782-1784. doi: 10.1016/j.annonc.2020.09.003. Epub 2020 Sep 14. PMID: 32941988. 10: Azaro A, Baldini C, Rodon J, Soria JC, Yuen E, Lithio A, Oakley G, Benhadji KA, Massard C. Phase 1 study of 2 high dose intensity schedules of the pan-Notch inhibitor crenigacestat (LY3039478) in combination with prednisone in patients with advanced or metastatic cancer. Invest New Drugs. 2021 Feb;39(1):193-201. doi: 10.1007/s10637-020-00944-z. Epub 2020 Sep 11. PMID: 32915419. 11: Mancarella S, Serino G, Coletta S, Armentano R, Dituri F, Ardito F, Ruzzenente A, Fabregat I, Giannelli G. The Tumor Microenvironment Drives Intrahepatic Cholangiocarcinoma Progression. Int J Mol Sci. 2022 Apr 10;23(8):4187. doi: 10.3390/ijms23084187. PMID: 35457006; PMCID: PMC9032805. 12: Zhou Z, Liu Y, Gao S, Zhou M, Qi F, Ding N, Zhang J, Li R, Wang J, Shi J, Yu R, Wang Y, Li Y, Pan J, Du J, Wang D. Excessive DNA damage mediates ECM degradation via the RBBP8/NOTCH1 pathway in sporadic aortic dissection. Biochim Biophys Acta Mol Basis Dis. 2022 Feb 1;1868(2):166303. doi: 10.1016/j.bbadis.2021.166303. Epub 2021 Nov 12. PMID: 34780912. 13: Azaro A, Massard C, Tap WD, Cassier PA, Merchan J, Italiano A, Anderson B, Yuen E, Yu D, Oakley G 3rd, Benhadji KA, Pant S. A phase 1b study of the Notch inhibitor crenigacestat (LY3039478) in combination with other anticancer target agents (taladegib, LY3023414, or abemaciclib) in patients with advanced or metastatic solid tumors. Invest New Drugs. 2021 Aug;39(4):1089-1098. doi: 10.1007/s10637-021-01094-6. Epub 2021 Mar 8. PMID: 33686452. 14: Yuen E, Posada M, Smith C, Thorn K, Greenwood D, Burgess M, A Benhadji K, Ortega D, Chinchen L, Suico J. Evaluation of the effects of an oral notch inhibitor, crenigacestat (LY3039478), on QT interval, and bioavailability studies conducted in healthy subjects. Cancer Chemother Pharmacol. 2019 Mar;83(3):483-492. doi: 10.1007/s00280-018-3750-1. Epub 2018 Dec 11. PMID: 30539232. 15: Even C, Lassen U, Merchan J, Le Tourneau C, Soria JC, Ferte C, Ricci F, Diener JT, Yuen E, Smith C, Oakley GJ 3rd, Benhadji KA, Massard C. Safety and clinical activity of the Notch inhibitor, crenigacestat (LY3039478), in an open- label phase I trial expansion cohort of advanced or metastatic adenoid cystic carcinoma. Invest New Drugs. 2020 Apr;38(2):402-409. doi: 10.1007/s10637-019-00739-x. Epub 2019 Apr 6. PMID: 30953269; PMCID: PMC7066312. 16: Lu L, Ma J, Liu Y, Shao Y, Xiong X, Duan W, Gao E, Yang Q, Chen S, Yang J, Ren J, Zheng Q, Liu J. FSTL1-USP10-Notch1 Signaling Axis Protects Against Cardiac Dysfunction Through Inhibition of Myocardial Fibrosis in Diabetic Mice. Front Cell Dev Biol. 2021 Dec 9;9:757068. doi: 10.3389/fcell.2021.757068. PMID: 34957094; PMCID: PMC8695978. 17: García-Guerrero E, Rodríguez-Lobato LG, Sierro-Martínez B, Danhof S, Bates S, Frenz S, Haertle L, Götz R, Sauer M, Rasche L, Kortüm KM, Pérez-Simón JA, Einsele H, Hudecek M, Prommersberger SR. All-trans retinoic acid works synergistically with the γ-secretase inhibitor crenigacestat to augment BCMA on multiple myeloma and the efficacy of BCMA-CAR T cells. Haematologica. 2023 Feb 1;108(2):568-580. doi: 10.3324/haematol.2022.281339. PMID: 36722406; PMCID: PMC9890012. 18: Doolittle WKL, Zhao L, Cheng SY. Blocking CDK7-Mediated NOTCH1-cMYC Signaling Attenuates Cancer Stem Cell Activity in Anaplastic Thyroid Cancer. Thyroid. 2022 Aug;32(8):937-948. doi: 10.1089/thy.2022.0087. PMID: 35822558; PMCID: PMC9419935. 19: Cowan AJ, Pont MJ, Sather BD, Turtle CJ, Till BG, Libby EN 3rd, Coffey DG, Tuazon SA, Wood B, Gooley T, Wu VQ, Voutsinas J, Song X, Shadman M, Gauthier J, Chapuis AG, Milano F, Maloney DG, Riddell SR, Green DJ. γ-Secretase inhibitor in combination with BCMA chimeric antigen receptor T-cell immunotherapy for individuals with relapsed or refractory multiple myeloma: a phase 1, first-in- human trial. Lancet Oncol. 2023 Jul;24(7):811-822. doi: 10.1016/S1470-2045(23)00246-2. PMID: 37414012. 20: Lu B, He Y, He J, Wang L, Liu Z, Yang J, Gao Z, Lu G, Zou C, Zhao W. Epigenetic Profiling Identifies LIF as a Super-enhancer-Controlled Regulator of Stem Cell-like Properties in Osteosarcoma. Mol Cancer Res. 2020 Jan;18(1):57-67. doi: 10.1158/1541-7786.MCR-19-0470. Epub 2019 Oct 15. PMID: 31615908.