CC-90011 besylate | CAS# 2097523-60-7 | LSD1 inhibitor

MedKoo Cat#: 207029 | Name: CC90011 besylate

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Description:

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

Pulrodemstat, also known as CC-90011, is a potent and orally active LSD1 inhibitor. CC-90011 binds to and inhibits LSD1, a demethylase that suppresses the expression of target genes by converting the di- and mono-methylated forms of lysine at position 4 of histone H3 (H3K4) to mono- and unmethylated H3K4, respectively. CC-90011 exhibits potent on-target induction of cellular differentiation in acute myeloid leukemia (AML) and small cell lung cancer (SCLC) cell lines, and antitumor efficacy in patient-derived xenograft (PDX) SCLC models.

Chemical Structure

CC90011 besylate

CAS#2097523-60-7 (besylate)

Theoretical Analysis

MedKoo Cat#: 207029

Name: CC90011 besylate

CAS#: 2097523-60-7 (besylate)

Chemical Formula: C30H29F2N5O5S

Exact Mass: 0.0000

Molecular Weight: 609.65

Elemental Analysis: C, 59.10; H, 4.79; F, 6.23; N, 11.49; O, 13.12; S, 5.26

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
1g	USD 4,950.00	2 Weeks

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Related CAS #

2097523-60-7 (besylate) 1821307-10-1 (free base) 2097523-57-2 (tosylate)

Synonym

Pulrodemstat besylate; CC-90011; CC90011; CC 90011; CC-90011 besylate;

IUPAC/Chemical Name

4-[2-(4-Amino-piperidin-1-yl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl]-2-fluorobenzonitrile benzenesulfonic acid

InChi Key

AWZCBGWZNHQCIZ-UHFFFAOYSA-N

InChi Code

InChI=1S/C24H23F2N5O2.C6H6O3S/c1-30-23(32)21(14-5-6-20(33-2)19(26)11-14)22(15-3-4-16(13-27)18(25)12-15)29-24(30)31-9-7-17(28)8-10-31;7-10(8,9)6-4-2-1-3-5-6/h3-6,11-12,17H,7-10,28H2,1-2H3;1-5H,(H,7,8,9)

SMILES Code

N#CC1=CC=C(C(N=C(N2CCC(N)CC2)N3C)=C(C4=CC=C(OC)C(F)=C4)C3=O)C=C1F.O=S(C5=CC=CC=C5)(O)=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

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

LSD1 has become an important biologically validated epigenetic target for cancer therapy since its identification in 2004. LSD1 mediates many cellular signaling pathways and is involved in the initiation and development of cancers. Aberrant overexpression of LSD1 has been observed in different types of cancers, and inactivation by small molecules suppresses cancer cell differentiation, proliferation, invasion and migration. To date, a large number of LSD1 inhibitors have been reported, RG6016, GSK-2879552, INCB059872, IMG-7289 and CC-90011 are currently undergoing clinical assessment for the treatment of acute myeloid leukemia, small-cell lung cancer, etc.

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot# A20T01K10

QC Data

View QC data: current batch, Lot# A20T01K10

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

CC-90011 benzenesulfonate is a potent, selective, reversible and orally active inhibitor of lysine specific demethylase-1 (LSD1) with an IC50 of 0.25 nM.

In vitro activity:

ChIP-seq analysis in SCLC cell lines (H69 and H209) showed LSD1 co-occupies sites with the enhancer mark H3K4me1 surrounding the GRP locus (Supporting Information) linking LSD1 to regulation of gastrin-releasing peptide (GRP) expression, which was used as a pharmacodynamic (PD) biomarker. Consistent with the ChIP-seq results, suppression of GRP was observed with treatment of CC90011 (compound 11) (4 days) in a dose-dependent manner and at pharmacologically useful concentrations (EC50 = 3 nM, H209 and 4 nM, H1417) (Figure 4A). In addition, treatment of SCLC cells with compound 11 for an extended incubation period (12 days) in vitro resulted in potent antiproliferative activity (EC50 = 6 nM, H1417) that correlated with GRP suppression (Figure 4B). It has been suggested that loss of GRP expression is a result of SCLC cells undergoing differentiation and losing their neuroendocrine status. Reference: J Med Chem. 2020 Dec 10;63(23):14522-14529. https://doi.org/10.1021/acs.jmedchem.0c00978

In vivo activity:

Compound 11 was advanced into a SCLC human tumor xenograft (H1417) study in mice. Mice were inoculated with H1417 tumor cells and treated QD at 2.5, 5, and 10 mg/kg of compound 11 for 4 consecutive days. GRP levels were assessed by qPCR 24 h after the last dose (Figure 4C). Treatment with compound 11 resulted in robust downregulation of GRP mRNA levels at 2.5 mg/kg and maximum suppression of GRP at 5 mg/kg. In a separate study, mice were implanted with H1417 SCLC tumors and treated with compound 11 daily at 2.5 and 5 mg/kg, which resulted in tumor growth regressions of 159% and 178%, respectively (P-value of 0.001 and 0.0001) (Figure 4D). Compound 11 was well tolerated for the duration of this study (65 days) with an average maximal body weight gain of up to 7% (Supporting Information). Maximum efficacy was observed at 5 mg/kg QD in both xenograft studies. These results established 5 mg/kg QD of 11 as the efficacious dose for the in vivo studies. To assess efficacy of compound 11 in clinically relevant patient-derived xenograft models (PDX), mice were inoculated with human LXFS 615 SCLC cells and treated with compound 11 at 5 mg/kg daily for 30 consecutive days. Compound treatment resulted in 78% TGI (P-value of 0.001) (Figure 5). Compound 11 was well tolerated with mean body weight loss of <1% (Supporting Information). The efficacy observed in this PDX model is in line with other SCLC PDX models that had been treated with compound 11. Reference: J Med Chem. 2020 Dec 10;63(23):14522-14529. https://doi.org/10.1021/acs.jmedchem.0c00978

	Solvent	mg/mL	mM
Solubility
	DMSO	62.5	102.52

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 609.65 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:

In vitro protocol:

1. Kanouni T, Severin C, Cho RW, Yuen NY, Xu J, Shi L, Lai C, Del Rosario JR, Stansfield RK, Lawton LN, Hosfield D, O'Connell S, Kreilein MM, Tavares-Greco P, Nie Z, Kaldor SW, Veal JM, Stafford JA, Chen YK. Discovery of CC-90011: A Potent and Selective Reversible Inhibitor of Lysine Specific Demethylase 1 (LSD1). J Med Chem. 2020 Dec 10;63(23):14522-14529. doi: 10.1021/acs.jmedchem.0c00978. Epub 2020 Oct 9. PMID: 33034194.

In vivo protocol:

1: Bandini C, Mereu E, Paradzik T, Labrador M, Maccagno M, Cumerlato M, Oreglia F, Prever L, Manicardi V, Taiana E, Ronchetti D, D'Agostino M, Gay F, Larocca A, Besse L, Merlo GR, Hirsch E, Ciarrocchi A, Inghirami G, Neri A, Piva R. Lysin (K)-specific demethylase 1 inhibition enhances proteasome inhibitor response and overcomes drug resistance in multiple myeloma. Exp Hematol Oncol. 2023 Aug 10;12(1):71. doi: 10.1186/s40164-023-00434-x. PMID: 37563685; PMCID: PMC10413620. 2: Zhang C, Wang Z, Shi Y, Yu B, Song Y. Recent advances of LSD1/KDM1A inhibitors for disease therapy. Bioorg Chem. 2023 May;134:106443. doi: 10.1016/j.bioorg.2023.106443. Epub 2023 Feb 24. PMID: 36857932. 3: Noce B, Di Bello E, Fioravanti R, Mai A. LSD1 inhibitors for cancer treatment: Focus on multi-target agents and compounds in clinical trials. Front Pharmacol. 2023 Feb 2;14:1120911. doi: 10.3389/fphar.2023.1120911. PMID: 36817147; PMCID: PMC9932783. 4: Hollebecque A, Salvagni S, Plummer R, Niccoli P, Capdevila J, Curigliano G, Moreno V, de Braud F, de Villambrosia SG, Martin-Romano P, Baudin E, Arias M, de Alvaro J, Parra-Palau JL, Sánchez-Pérez T, Aronchik I, Filvaroff EH, Lamba M, Nikolova Z, de Bono JS. Clinical activity of CC-90011, an oral, potent, and reversible LSD1 inhibitor, in advanced malignancies. Cancer. 2022 Sep 1;128(17):3185-3195. doi: 10.1002/cncr.34366. Epub 2022 Jun 23. PMID: 35737639; PMCID: PMC9540525. 5: Sacilotto N, Dessanti P, Lufino MMP, Ortega A, Rodríguez-Gimeno A, Salas J, Maes T, Buesa C, Mascaró C, Soliva R. Comprehensive in Vitro Characterization of the LSD1 Small Molecule Inhibitor Class in Oncology. ACS Pharmacol Transl Sci. 2021 Nov 12;4(6):1818-1834. doi: 10.1021/acsptsci.1c00223. PMID: 34927013; PMCID: PMC8669716. 6: Dai XJ, Liu Y, Xue LP, Xiong XP, Zhou Y, Zheng YC, Liu HM. Reversible Lysine Specific Demethylase 1 (LSD1) Inhibitors: A Promising Wrench to Impair LSD1. J Med Chem. 2021 Mar 11;64(5):2466-2488. doi: 10.1021/acs.jmedchem.0c02176. Epub 2021 Feb 23. Erratum in: J Med Chem. 2021 May 13;64(9):6410-6411. PMID: 33619958. 7: Hollebecque A, Salvagni S, Plummer R, Isambert N, Niccoli P, Capdevila J, Curigliano G, Moreno V, Martin-Romano P, Baudin E, Arias M, Mora S, de Alvaro J, Di Martino J, Parra-Palau JL, Sánchez-Pérez T, Aronchik I, Filvaroff EH, Lamba M, Nikolova Z, de Bono JS. Phase I Study of Lysine-Specific Demethylase 1 Inhibitor, CC-90011, in Patients with Advanced Solid Tumors and Relapsed/Refractory Non-Hodgkin Lymphoma. Clin Cancer Res. 2021 Jan 15;27(2):438-446. doi: 10.1158/1078-0432.CCR-20-2380. Epub 2020 Oct 12. PMID: 33046517. 8: Kanouni T, Severin C, Cho RW, Yuen NY, Xu J, Shi L, Lai C, Del Rosario JR, Stansfield RK, Lawton LN, Hosfield D, O'Connell S, Kreilein MM, Tavares-Greco P, Nie Z, Kaldor SW, Veal JM, Stafford JA, Chen YK. Discovery of CC-90011: A Potent and Selective Reversible Inhibitor of Lysine Specific Demethylase 1 (LSD1). J Med Chem. 2020 Dec 10;63(23):14522-14529. doi: 10.1021/acs.jmedchem.0c00978. Epub 2020 Oct 9. PMID: 33034194. 9: Fang Y, Liao G, Yu B. LSD1/KDM1A inhibitors in clinical trials: advances and prospects. J Hematol Oncol. 2019 Dec 4;12(1):129. doi: 10.1186/s13045-019-0811-9. PMID: 31801559; PMCID: PMC6894138. 10: Fu X, Zhang P, Yu B. Advances toward LSD1 inhibitors for cancer therapy. Future Med Chem. 2017 Jul;9(11):1227-1242. doi: 10.4155/fmc-2017-0068. Epub 2017 Jul 19. PMID: 28722477.