Crenigacestat
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MedKoo CAT#: 206102

CAS#: 1421438-81-4

Description: 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

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Crenigacestat
CAS# 1421438-81-4

Theoretical Analysis

MedKoo Cat#: 206102
Name: Crenigacestat
CAS#: 1421438-81-4
Chemical Formula: C22H23F3N4O4
Exact Mass: 464.16714
Molecular Weight: 464.43763
Elemental Analysis: C, 56.89; H, 4.99; F, 12.27; N, 12.06; O, 13.78

Price and Availability

Size Price Availability Quantity
5.0mg USD 90.0 Same day
10.0mg USD 150.0 Same day
25.0mg USD 250.0 Same day
50.0mg USD 450.0 Same day
100.0mg USD 750.0 Same day
200.0mg USD 1250.0 Same day
500.0mg USD 2650.0 Same day
1.0g USD 3950.0 Same day
2.0g USD 6150.0 2 Weeks
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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

Preparing Stock Solutions

The following data is based on the product molecular weight 464.43763 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

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1: 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. 2020 Oct 27. doi: 10.1002/cncr.33188. Epub ahead of print. PMID: 33107983.

2: 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 Sep 14:S0923-7534(20)42444-5. doi: 10.1016/j.annonc.2020.09.003. Epub ahead of print. PMID: 32941988.

3: 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. 2020 Sep 16. doi: 10.1007/s10637-020-01001-5. Epub ahead of print. PMID: 32939607.

4: 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. 2020 Sep 11. doi: 10.1007/s10637-020-00944-z. Epub ahead of print. PMID: 32915419.

5: 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.

6: Yang M, Zhang G, Wang Y, He M, Xu Q, Lu J, Liu H, Xu C. Tumour-associated neutrophils orchestrate intratumoural IL-8-driven immune evasion through Jagged2 activation in ovarian cancer. Br J Cancer. 2020 Oct;123(9):1404-1416. doi: 10.1038/s41416-020-1026-0. Epub 2020 Aug 11. PMID: 32778818.

7: 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.

8: 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.

9: 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.

10: Ye K, He D, Shao Y, Xu N, Jin C, Zhang L, Shen J. Exogenous mesenchymal stem cells affect the function of endogenous lung stem cells (club cells) in phosgene-induced lung injury. Biochem Biophys Res Commun. 2019 Jun 30;514(3):586-592. doi: 10.1016/j.bbrc.2019.04.182. Epub 2019 May 4. PMID: 31064653.

11: 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.

12: 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.

13: Mir O, Azaro A, Merchan J, Chugh R, Trent J, Rodon J, Ohnmacht U, Diener JT, Smith C, Yuen E, Oakley GJ 3rd, Le Cesne A, Soria JC, Benhadji KA, Massard C. Notch pathway inhibition with LY3039478 in soft tissue sarcoma and gastrointestinal stromal tumours. Eur J Cancer. 2018 Nov;103:88-97. doi: 10.1016/j.ejca.2018.08.012. Epub 2018 Sep 12. PMID: 30218977.

14: Massard C, Azaro A, Soria JC, Lassen U, Le Tourneau C, Sarker D, Smith C, Ohnmacht U, Oakley G, Patel BKR, Yuen ESM, Benhadji KA, Rodon J. First-in-human study of LY3039478, an oral Notch signaling inhibitor in advanced or metastatic cancer. Ann Oncol. 2018 Sep 1;29(9):1911-1917. doi: 10.1093/annonc/mdy244. PMID: 30060061.

15: 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.

16: Notch Inhibitor Shows Modest Efficacy. Cancer Discov. 2017 Feb;7(2):OF3. doi: 10.1158/2159-8290.CD-NB2016-159. Epub 2016 Dec 14. PMID: 27974417.

17: Bhagat TD, Zou Y, Huang S, Park J, Palmer MB, Hu C, Li W, Shenoy N, Giricz O, Choudhary G, Yu Y, Ko YA, Izquierdo MC, Park AS, Vallumsetla N, Laurence R, Lopez R, Suzuki M, Pullman J, Kaner J, Gartrell B, Hakimi AA, Greally JM, Patel B, Benhadji K, Pradhan K, Verma A, Susztak K. Notch Pathway Is Activated via Genetic and Epigenetic Alterations and Is a Therapeutic Target in Clear Cell Renal Cancer. J Biol Chem. 2017 Jan 20;292(3):837-846. doi: 10.1074/jbc.M116.745208. Epub 2016 Dec 1. PMID: 27909050; PMCID: PMC5247657.



Additional Information

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