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CC-92480 Sale

(Synonyms: CC-92480) 目录号 : GC39169

A modulator of cereblon

CC-92480 Chemical Structure

Cas No.:2259648-80-9

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产品描述

CC-92480 is a modulator of the E3 ligase cereblon.1 It binds to cereblon (IC50 = 0.03 ?M in a FRET assay) and induces the degradation of Ikaros and Aiolos in lenalidomide-resistant H929 R10-1 cells when used at concentrations of 1, 10, and 100 nM. CC-92480 induces apoptosis in the same cells. It reduces tumor growth in an H929 R10-1 mouse xenograft model when administered at doses of 1, 3, and 10 mg/kg.

1.Hansen, J.D., Correa, M., Nagy, M.A., et al.Discovery of CRBN E3 ligase modulator CC-92480 for the treatment of relapsed and refractory multiple myelomaJ. Med. Chem.63(13)6648-6676(2020)

Chemical Properties

Cas No. 2259648-80-9 SDF
别名 CC-92480
Canonical SMILES N#CC1=CC=C(N2CCN(CC3=CC=C(COC4=CC=CC5=C4CN([C@@H](CC6)C(NC6=O)=O)C5=O)C=C3)CC2)C(F)=C1
分子式 C32H30FN5O4 分子量 567.61
溶解度 DMSO: 5 mg/mL (8.81 mM; ultrasonic and warming and heat to 60°C) 储存条件 Store at -20°C
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1 mM 1.7618 mL 8.8089 mL 17.6177 mL
5 mM 0.3524 mL 1.7618 mL 3.5235 mL
10 mM 0.1762 mL 0.8809 mL 1.7618 mL
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Research Update

Discovery of CRBN E3 Ligase Modulator CC-92480 for the Treatment of Relapsed and Refractory Multiple Myeloma

J Med Chem 2020 Jul 9;63(13):6648-6676.PMID:32130004DOI:10.1021/acs.jmedchem.9b01928.

Many patients with multiple myeloma (MM) initially respond to treatment with modern combination regimens including immunomodulatory agents (lenalidomide and pomalidomide) and proteasome inhibitors. However, some patients lack an initial response to therapy (i.e., are refractory), and although the mean survival of MM patients has more than doubled in recent years, most patients will eventually relapse. To address this need, we explored the potential of novel cereblon E3 ligase modulators (CELMoDs) for the treatment of patients with relapsed or refractory multiple myeloma (RRMM). We found that optimization beyond potency of degradation, including degradation efficiency and kinetics, could provide efficacy in a lenalidomide-resistant setting. Guided by both phenotypic and protein degradation data, we describe a series of CELMoDs for the treatment of RRMM, culminating in the discovery of CC-92480, a novel protein degrader and the first CELMoD to enter clinical development that was specifically designed for efficient and rapid protein degradation kinetics.

Overcoming IMiD resistance in T-cell lymphomas through potent degradation of ZFP91 and IKZF1

Blood 2022 Mar 31;139(13):2024-2037.PMID:34936696DOI:10.1182/blood.2021014701.

Immunomodulatory (IMiD) agents like lenalidomide and pomalidomide induce the recruitment of IKZF1 and other targets to the CRL4CRBN E3 ubiquitin ligase, resulting in their ubiquitination and degradation. These agents are highly active in B-cell lymphomas and a subset of myeloid diseases but have compromised effects in T-cell lymphomas (TCLs). Here, we show that 2 factors determine resistance to IMiDs among TCLs. First, limited CRBN expression reduces IMiD activity in TCLs but can be overcome by newer-generation degrader CC-92480. Using mass spectrometry, we show that CC-92480 selectively degrades IKZF1 and ZFP91 in TCL cells with greater potency than pomalidomide. As a result, CC-92480 is highly active against multiple TCL subtypes and showed greater efficacy than pomalidomide across 4 in vivo TCL models. Second, we demonstrate that ZFP91 functions as a bona fide transcription factor that coregulates cell survival with IKZF1 in IMiD-resistant TCLs. By activating keynote genes from WNT, NF-kB, and MAP kinase signaling, ZFP91 directly promotes resistance to IKZF1 loss. Moreover, lenalidomide-sensitive TCLs can acquire stable resistance via ZFP91 rewiring, which involves casein kinase 2-mediated c-Jun inactivation. Overall, these findings identify a critical transcription factor network within TCLs and provide clinical proof of concept for the novel therapy using next-generation degraders.

Pharmacokinetics, bioavailability and metabolism of CC-92480 in rat by liquid chromatography combined with electrospray ionization tandem mass spectrometry

Biomed Chromatogr 2021 Sep;35(9):e5139.PMID:33830533DOI:10.1002/bmc.5139.

CC-92480 is a cereblon E3 ubiquitin ligase modulating drug with potent antimyeloma activity. In this study, we developed a sensitive UHPLC-MS/MS method for the determination of CC-92480 in rat plasma. The plasma samples were prepared with acetonitrile and the samples were then separated on an Acquity BEH C18 column (2.1 × 50 mm, 1.7 μm) with water containing 0.1% formic acid (A) and acetonitrile (B) as mobile phase. The MS detection was performed using multiple reaction monitoring mode with precursor-to-product ion transitions at m/z 568.3 > 363.1 for CC-92480 and m/z 441.2 > 138.1 for ibrutinib (internal standard). The assay showed excellent linearity over the concentration range of 1-1,000 ng/ml, with correlation coefficient >0.995. The method was further validated for selectivity, precision, accuracy, recovery and stability according to the US Food and Drug Administration's guideline. The validated method was successfully applied to the pharmacokinetic and bioavailability studies of CC-92480 in rat plasma. Based on the pharmacokinetic results, the oral bioavailability of CC-92480 was >63%. In addition, the circulating metabolites of CC-92480 were detected by UHPLC-HRMS and the structures were proposed according to their accurate masses and fragment ions. The proposed metabolic pathways of CC-92480 were oxidative dealkylation and amide hydrolysis.

Targeting cereblon in hematologic malignancies

Blood Rev 2023 Jan;57:100994.PMID:35933246DOI:10.1016/j.blre.2022.100994.

The protein cereblon (CRBN) is a substrate receptor of the cullin 4-really interesting new gene (RING) E3 ubiquitin ligase complex CRL4CRBN. Targeting CRBN mediates selective protein ubiquitination and subsequent degradation via the proteasome. This review describes novel thalidomide analogs, immunomodulatory drugs, also known as CRBN E3 ubiquitin ligase modulators or molecular glues (avadomide, iberdomide, CC-885, CC-90009, BTX-1188, CC-92480, CC-99282, CFT7455, and CC-91633), and CRBN-based proteolysis targeting chimeras (PROTACs) with increased efficacy and potent activity for application in hematologic malignancies. Both types of CRBN-binding drugs, molecular glues, and PROTACs stimulate the interaction between CRBN and its neosubstrates, recruiting target disease-promoting proteins and the E3 ubiquitin ligase CRL4CRBN. Proteins that are traditionally difficult to target (transcription factors and oncoproteins) can be polyubiquitinated and degraded in this way. The competition of CRBN neosubstrates with endogenous CRBN-interacting proteins and the pharmacology and rational combination therapies of and mechanisms of resistance to CRL4CRBN modulators or CRBN-based PROTACs are described.

Developing next generation immunomodulatory drugs and their combinations in multiple myeloma

Oncotarget 2021 Jul 20;12(15):1555-1563.PMID:34316334DOI:10.18632/oncotarget.27973.

Multiple Myeloma (MM) is an incurable malignancy with current treatment choices primarily comprising combination regimens implemented with a risk-adapted approach. Cereblon (CRBN)-targeting immunomodulatory agents (IMiDs®) lenalidomide (LEN) and pomalidomide (POM) play a central role in combination regimens due to their pleiotropic antitumor/immunomodulatory mechanisms that synergize with many anti-myeloma approved or developmental agents. Currently, more potent next generation cereblon E3 ligase modulators (CELMoDs®) - iberdomide (IBER) and CC-92480 are in clinical development. With an expanding number of active agents/therapeutic modalities and a myriad of combinatorial possibilities, physicians and drug developers share an opportunity and challenge to combine and sequence therapies to maximize long-term patient benefit. Understanding drug mechanisms and their application in combination settings as well as the unique disease biology considerations from newly diagnosed (NDMM), relapsed/refractory (RRMM), and maintenance settings will be vital to guide the development of future MM therapies centered on a backbone of IMiD or CELMoD agents. Key aspects of drug activity are critical to consider while evaluating potential combinations: direct antitumor effects, indirect antitumor cytotoxicity, immune surveillance, and adverse side effects. In addition, the treatment journey from NDMM to early and late MM relapses are connected to genomic and immune changes associated with disease progression and acquisition of resistance mechanisms. Based on the types of combinations used and the goals of therapy, insights into mechanisms of drug activity and resistance may inform treatment decisions for patients with MM. Here we focus on the evolving understanding of the molecular mechanisms of CRBN-binding drugs and how they can be differentiated and suggest a strategic framework to optimize efficacy and safety of combinations using these agents.