CC-122 | Avadomide free base | CAS#1015474-32-4 | pleiotropic pathway modulator

MedKoo Cat#: 205830 | Name: Avadomide free base

Description:

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

Avadomide, also known as CC-122, is an orally available pleiotropic pathway modulator with potential antineoplastic activity. CC-122 mimics an interferon response and has antitumor activity in DLBCL CC-122 binds Cereblon (CRBN) and promotes degradation of Aiolos and Ikaros in diffuse large B-cell lymphoma (DLBCL) and T cells in vitro, in vivo, and in patients, resulting in both cell autonomous as well as immunostimulatory effects.

Chemical Structure

Avadomide free base

CAS#1015474-32-4 (free base)

Theoretical Analysis

MedKoo Cat#: 205830

Name: Avadomide free base

CAS#: 1015474-32-4 (free base)

Chemical Formula: C14H14N4O3

Exact Mass: 286.1066

Molecular Weight: 286.29

Elemental Analysis: C, 58.74; H, 4.93; N, 19.57; O, 16.77

Price and Availability

Size	Price	Availability
10mg	USD 150.00	Ready to ship
25mg	USD 250.00	Ready to ship
50mg	USD 450.00	Ready to ship
100mg	USD 750.00	Ready to ship
200mg	USD 1,250.00	Ready to ship
500mg	USD 2,150.00	Ready to ship
1g	USD 3,150.00	Ready to ship
2g	USD 5,250.00	Ready to ship

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Related CAS #

1398053-45-6 (HCl) 1015474-32-4 (free base)

Synonym

CC 122; CC-122; CC122, Avadomide

IUPAC/Chemical Name

3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione

InChi Key

RSNPAKAFCAAMBH-UHFFFAOYSA-N

InChi Code

InChI=1S/C14H14N4O3/c1-7-16-9-4-2-3-8(15)12(9)14(21)18(7)10-5-6-11(19)17-13(10)20/h2-4,10H,5-6,15H2,1H3,(H,17,19,20)

SMILES Code

O=C(C(N1C(C)=NC2=C(C(N)=CC=C2)C1=O)CC3)NC3=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

>5 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

In DLBCL cell lines, CC-122-induced degradation or short hairpin RNA-mediated knockdown of Aiolos and Ikaros correlates with increased transcription of interferon (IFN)-stimulated genes independent of IFN-α, -β, and -γ production and/or secretion and results in apoptosis in both activated B-cell (ABC) and germinal center B-cell DLBCL

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#B9B08C08

View CoA: current batch, Lot#B7B11C09

QC Data

View QC data: current batch, Lot#B9B08C08

View QC data: current batch, Lot#B7B11C09

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

Avadomide (CC 122) is an orally active cereblon modulator.

In vitro activity:

Antibody arrays revealed that avadomide, as well as its combination with anti-PD-1, induced the secretion of several proinflammatory (IL-2, tumor necrosis factor-α) and chemotactic cytokines (CXCL10, CCL5) (Figure 5A-B). In contrast, anti-PD-1 alone had little effect on the production of cytokines from xenografted patient T cells. Multiplex immunoassays confirmed the consistent enrichment of immunoregulatory and chemoattractant cytokines including CXCL10 within the culture supernatants of T cells treated with avadomide alone or in combination with anti-PD-1 or anti-PD-L1 (including significantly increased CXCL10 production with combination therapy compared with avadomide alone) (Figure 5C). Time-lapse microscopy assays showed that avadomide, as well as anti-PD-1 or anti-PD-L1 alone, enhanced T-cell motility compared with vehicle treatment (Figure 5D). However, compared with these drugs alone, avadomide plus anti-PD-1 or anti-PD-L1 increased T-cell migration rates. The conditioned media of avadomide-treated T cells increased the recruitment of T cells, which was further enhanced when avadomide was paired with PD-L1/PD-1 blockade (Figure 5E). This augmented T-cell migration was reduced by cotreating xenografted patient T cells with a neutralizing antibody targeting CXCR3, the receptor for CXCL9-11 (Figure 5F). Collectively, data suggest that the ability of avadomide to activate IFN-activated chemokine and cytoskeletal signaling in patient T cells could enhance the recruitment and functionality of immune cells in the TME. Reference: Blood. 2021 Jan 14; 137(2): 216–231. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820876/

In vivo activity:

Mice with established tumors (3 weeks after xenografting) were treated with a single dose of avadomide or anti-PD-L1 alone or in combination for 6 days. The splenic TME, the percentage of CD25+ CD8+ T cells increased following avadomide and combination anti-PD-L1 therapy (Figure 6A). In contrast, this stimulatory effect was less evident in the patient CD4+ T-cell compartment (supplemental Figure 6A). Notably, avadomide therapy increased the frequency of PD-L1+ CD8+ T cells and CLL cells (Figure 6B; supplemental Figure 6C), whereas expression of PD-1 did not change (supplemental Figure 6B). Confocal microscopy corroborated the ability of avadomide to induce PD-L1 expression within the immune TME (Figure 6C) and triggered CD8+ T cells to increase in number and infiltrate tumor areas more vigorously (Figure 6D). CD4+ T cells localized mainly within CLL nodules at baseline (vehicle) intermixed with tumor cells, in keeping with their pro-tumor role. In contrast, CD8+ T cells exhibited a tumor-excluded localization pattern at baseline that converted to a tumor-infiltrated pattern following avadomide treatment, maximally augmented with combination therapy. Reference: Blood. 2021 Jan 14; 137(2): 216–231. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820876/

	Solvent	mg/mL	mM
Solubility
	DMSO	40.1	140.10
	DMSO:PBS (pH 7.2) (1:1)	0.3	1.15
	DMF	30.0	104.79

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 286.29 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:

Ioannou N, Hagner PR, Stokes M, Gandhi AK, Apollonio B, Fanous M, Papazoglou D, Sutton LA, Rosenquist R, Amini RM, Chiu H, Lopez-Girona A, Janardhanan P, Awan FT, Jones J, Kay NE, Shanafelt TD, Tallman MS, Stamatopoulos K, Patten PEM, Vardi A, Ramsay AG. Triggering interferon signaling in T cells with avadomide sensitizes CLL to anti-PD-L1/PD-1 immunotherapy. Blood. 2021 Jan 14;137(2):216-231. doi: 10.1182/blood.2020006073. PMID: 33024998; PMCID: PMC7820876.

In vitro protocol:

In vivo protocol:

1: Tsang M, Cleveland J, Rubenstein JL. On point in primary CNS lymphoma. Hematol Oncol. 2020 Dec;38(5):640-647. doi: 10.1002/hon.2761. Epub 2020 Jul 3. PMID: 32510610; PMCID: PMC8815361. 2: Renneville A, Gasser JA, Grinshpun DE, Jean Beltran PM, Udeshi ND, Matyskiela ME, Clayton T, McConkey M, Viswanathan K, Tepper A, Guirguis AA, Sellar RS, Cotteret S, Marzac C, Saada V, De Botton S, Kiladjian JJ, Cayuela JM, Rolfe M, Chamberlain PP, Carr SA, Ebert BL. Avadomide induces degradation of ZMYM2 fusion oncoproteins in hematologic malignancies. Blood Cancer Discov. 2021 May;2(3):250-265. doi: 10.1158/2643-3230.BCD-20-0105. Epub 2021 Mar 10. PMID: 34027417; PMCID: PMC8133393. 3: Fuchs O. Targeting cereblon in hematologic malignancies. Blood Rev. 2023 Jan;57:100994. doi: 10.1016/j.blre.2022.100994. Epub 2022 Jul 31. PMID: 35933246. 4: Carpio C, Bouabdallah R, Ysebaert L, Sancho JM, Salles G, Cordoba R, Pinto A, Gharibo M, Rasco D, Panizo C, Lopez-Martin JA, Santoro A, Salar A, Damian S, Martin A, Verhoef G, Van den Neste E, Wang M, Couto S, Carrancio S, Weng A, Wang X, Schmitz F, Wei X, Hege K, Trotter MWB, Risueño A, Buchholz TJ, Hagner PR, Gandhi AK, Pourdehnad M, Ribrag V. Avadomide monotherapy in relapsed/refractory DLBCL: safety, efficacy, and a predictive gene classifier. Blood. 2020 Mar 26;135(13):996-1007. doi: 10.1182/blood.2019002395. Erratum in: Blood. 2021 Apr 15;137(15):2126. PMID: 31977002; PMCID: PMC7099331. 5: Nastoupil LJ, Kuruvilla J, Chavez JC, Bijou F, Witzig TE, Santoro A, Flinn IW, Boccomini C, Kenkre VP, Corradini P, Isufi I, Andorsky DJ, Klein LM, Greenwald DR, Sangha R, Shen F, Hagner P, Li Y, Dobmeyer J, Gong N, Uttamsingh S, Pourdehnad M, Ribrag V. Phase Ib study of avadomide (CC-122) in combination with rituximab in patients with relapsed/refractory diffuse large B-cell lymphoma and follicular lymphoma. EJHaem. 2022 Feb 14;3(2):394-405. doi: 10.1002/jha2.394. PMID: 35846031; PMCID: PMC9175947. 6: Michot JM, Bouabdallah R, Vitolo U, Doorduijn JK, Salles G, Chiappella A, Zinzani PL, Bijou F, Kersten MJ, Sarmiento R, Mosulen S, Mendez C, Uttamsingh S, Pourdehnad M, Hege K, Chen T, Klein C, Hagner PR, Nikolova Z, Ribrag V. Avadomide plus obinutuzumab in patients with relapsed or refractory B-cell non- Hodgkin lymphoma (CC-122-NHL-001): a multicentre, dose escalation and expansion phase 1 study. Lancet Haematol. 2020 Sep;7(9):e649-e659. doi: 10.1016/S2352-3026(20)30208-8. Epub 2020 Aug 3. PMID: 32758434. 7: Abbiati RA, Pourdehnad M, Carrancio S, Pierce DW, Kasibhatla S, McConnell M, Trotter MWB, Loos R, Santini CC, Ratushny AV. Quantitative Systems Pharmacology Modeling of Avadomide-Induced Neutropenia Enables Virtual Clinical Dose and Schedule Finding Studies. AAPS J. 2021 Aug 27;23(5):103. doi: 10.1208/s12248-021-00623-8. Erratum in: AAPS J. 2022 Jan 14;24(1):29. PMID: 34453265; PMCID: PMC8397660. 8: Ioannou N, Hagner PR, Stokes M, Gandhi AK, Apollonio B, Fanous M, Papazoglou D, Sutton LA, Rosenquist R, Amini RM, Chiu H, Lopez-Girona A, Janardhanan P, Awan FT, Jones J, Kay NE, Shanafelt TD, Tallman MS, Stamatopoulos K, Patten PEM, Vardi A, Ramsay AG. Triggering interferon signaling in T cells with avadomide sensitizes CLL to anti-PD-L1/PD-1 immunotherapy. Blood. 2021 Jan 14;137(2):216-231. doi: 10.1182/blood.2020006073. PMID: 33024998; PMCID: PMC7820876. 9: Rasco DW, Papadopoulos KP, Pourdehnad M, Gandhi AK, Hagner PR, Li Y, Wei X, Chopra R, Hege K, DiMartino J, Shih K. A First-in-Human Study of Novel Cereblon Modulator Avadomide (CC-122) in Advanced Malignancies. Clin Cancer Res. 2019 Jan 1;25(1):90-98. doi: 10.1158/1078-0432.CCR-18-1203. Epub 2018 Sep 10. PMID: 30201761. 10: Hatake K, Chou T, Doi T, Terui Y, Kato H, Hirose T, Seo S, Pourdehnad M, Ogaki Y, Fujimoto H, Hagner PR, Yamamoto K. Phase I, multicenter, dose- escalation study of avadomide in adult Japanese patients with advanced malignancies. Cancer Sci. 2021 Jan;112(1):331-338. doi: 10.1111/cas.14704. Epub 2020 Nov 26. PMID: 33075165; PMCID: PMC7780008. 11: Ribrag V, Chavez JC, Boccomini C, Kaplan J, Chandler JC, Santoro A, Corradini P, Flinn IW, Advani R, Cassier PA, Sangha R, Kenkre VP, Isufi I, Uttamsingh S, Hagner PR, Gandhi AK, Shen F, Michelliza S, Haeske H, Hege K, Pourdehnad M, Kuruvilla J. Phase Ib study of combinations of avadomide (CC-122), CC-223, CC-292, and rituximab in patients with relapsed/refractory diffuse large B-cell lymphoma. EJHaem. 2022 Jan 14;3(1):139-153. doi: 10.1002/jha2.375. PMID: 35846221; PMCID: PMC9176062. 12: Heim C, Hartmann MD. High-resolution structures of the bound effectors avadomide (CC-122) and iberdomide (CC-220) highlight advantages and limitations of the MsCI4 soaking system. Acta Crystallogr D Struct Biol. 2022 Mar 1;78(Pt 3):290-298. doi: 10.1107/S2059798322000092. Epub 2022 Feb 18. PMID: 35234143; PMCID: PMC8900816. 13: Abbiati RA, Pourdehnad M, Carrancio S, Pierce DW, Kasibhatla S, McConnell M, Trotter MWB, Loos R, Santini CC, Ratushny AV. Correction to: Quantitative Systems Pharmacology Modeling of Avadomide-Induced Neutropenia Enables Virtual Clinical Dose and Schedule Finding Studies. AAPS J. 2022 Jan 14;24(1):29. doi: 10.1208/s12248-021-00673-y. Erratum for: AAPS J. 2021 Aug 27;23(5):103. PMID: 35038051; PMCID: PMC9172776. 14: Ogasawara K, MacGorman K, Liu L, Chen J, Carayannopoulos LN, Zhou S, Palmisano M, Li Y. Drug-Drug Interaction Study to Assess the Effect of Cytochrome P450 Inhibition and Induction on the Pharmacokinetics of the Novel Cereblon Modulator Avadomide (CC-122) in Healthy Adult Subjects. J Clin Pharmacol. 2019 Dec;59(12):1620-1631. doi: 10.1002/jcph.1453. Epub 2019 Jun 6. PMID: 31172535; PMCID: PMC6851786. 15: Li Y, MacGorman K, Liu L, Chen J, Hoffmann M, Palmisano M, Zhou S. Single- Dose Pharmacokinetics, Safety, and Tolerability of Avadomide (CC-122) in Subjects With Mild, Moderate, or Severe Renal Impairment. Clin Pharmacol Drug Dev. 2020 Oct;9(7):785-796. doi: 10.1002/cpdd.760. Epub 2019 Dec 31. PMID: 31891240. 16: Carpio C, Bouabdallah R, Ysebaert L, et al. Avadomide monotherapy in relapsed/refractory DLBCL: safety, efficacy, and a predictive gene classifier. Blood. 2020;135(13):996-1007. Blood. 2021 Apr 15;137(15):2126. doi: 10.1182/blood.2021011546. Erratum for: Blood. 2020 Mar 26;135(13):996-1007. PMID: 33856449; PMCID: PMC8057265. 17: Yamshon S, Ruan J. IMiDs New and Old. Curr Hematol Malig Rep. 2019 Oct;14(5):414-425. doi: 10.1007/s11899-019-00536-6. PMID: 31302872. 18: Ito T, Handa H. [Cereblon as a primary target of IMiDs]. Rinsho Ketsueki. 2019;60(9):1013-1019. Japanese. doi: 10.11406/rinketsu.60.1013. PMID: 31597822. 19: Hagner PR, Chiu H, Chopra VS, Colombo M, Patel N, Estevez MO, Waldman MF, Loos R, Towfic F, Gandhi AK. Interactome of Aiolos/Ikaros Reveals Combination Rationale of Cereblon Modulators with HDAC Inhibitors in DLBCL. Clin Cancer Res. 2022 Aug 2;28(15):3367-3377. doi: 10.1158/1078-0432.CCR-21-3347. PMID: 35583604; PMCID: PMC9662945. 20: Ioannou N, Jain K, Ramsay AG. Immunomodulatory Drugs for the Treatment of B Cell Malignancies. Int J Mol Sci. 2021 Aug 9;22(16):8572. doi: 10.3390/ijms22168572. PMID: 34445275; PMCID: PMC8395307.