Cereblon; IKZF1; IKZF3 (Kd = 0.9 nM)
CFT7455 is a novel degrader targeting Ikaros family zinc finger proteins IKZF1 and IKZF3. It induces degradation of IKZF1/3 through high-affinity binding to cereblon (CRBN), a component of the CRL4-CRBN E3 ubiquitin ligase complex [2].

CFT7455 demonstrated an 800-fold improvement in CRBN binding in biochemical assays and a 1,600-fold improvement in cellular NanoBRET assays compared to pomalidomide [2].
In H929 multiple myeloma cells expressing HiBiT-tagged IKZF1, CFT7455 induced over 75% degradation of IKZF1 within 1.5 hours [2].
CFT7455 exhibited potent antiproliferative activity across a panel of multiple myeloma cell lines, as well as in H929 cells that had acquired resistance to immunomodulatory drugs (IMiDs) [2].

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In multiple myeloma cells, cemsidomide stimulates the degradation of >75% of steady-state IKZF1 in 1.5 hours at 0.3 nM. Both NCIH929 cells resistant to both lenalidomide and pomalidomide (IC50 of 2.3 nM) and previously untreated NCIH929 multiple myeloma cell lines (IC50 of 0.071 nM) are efficiently inhibited by the strong binding affinity and degradation catalysis of CFT7455 [1]. When applied to IMiD-resistant H929 cells and multiple myeloma cells, cemsidomide exhibits strong antiproliferative action [2].

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Cemsidomide is a cereblon E3 ubiquitin ligase modulator that induces the degradation of Ikaros (IKZF1) and Aiolos (IKZF3), leading to T-cell activation and increased production of IL-2 and IFN-γ in PBMC cultures. It exerts single-agent pro-apoptotic activity and demonstrates significant synergy with other agents. Notably, cemsidomide remains effective in cell lines resistant to other immunomodulatory drugs such as CC-4047, CC-5013, and CC-220 .

RPMI-8226 Mouse Xenograft Model: In mice bearing RPMI-8226 xenografts, treatment with CFT7455 (0.1 mg/kg/day) resulted in deep and durable degradation of IKZF3, with protein levels reduced to 21% and 9.5% of vehicle control at 4 hours and 24 hours post-dose, respectively. IRF4 protein levels declined to 8% of vehicle levels over 7 days of daily treatment. Dose-dependent efficacy was observed across a range of 0.003 to 0.1 mg/kg/day, with tumor regression evident at doses ≥0.01 mg/kg/day. In this model, pomalidomide was inactive at a human equivalent dose of 3 mg/kg/day, with no observed tumor shrinkage after 17 days. Switching from pomalidomide to CFT7455 (0.1 mg/kg/day) on day 18 led to tumor regression in 67% of animals by day 28 and 100% tumor regression by day 35 [2].
H929 Tumor Xenograft Model: In mice bearing H929 tumor xenografts, administration of CFT7455 (0.1 mg/kg/day) promoted tumor regression with 95% tumor growth inhibition by day 7. Dosing was stopped after 21 days. By day 63, half of the tumors remained below their starting tumor volume [2].
MM1.S Systemic Tumor Model: CFT7455 demonstrated durable tumor regression in the aggressive MM1.S systemic multiple myeloma model [2].
Combination with Dexamethasone: In mice bearing RPMI-8226 xenografts, the combination of CFT7455 (daily dosing) and dexamethasone (weekly dosing) was more active than either agent alone and demonstrated a significant improvement in survival [2].

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Cemsidomide showed dose-dependent effectiveness in mice xenograft tumor models, with doses ranging from 3 μg/kg/day to 100 μg/kg/day. In many tumor xenograft experiments, cemsidomide administered daily at doses ranging from 30 μg/kg/day to 100 μg/kg/day produced long-lasting tumor regression [1]. In a H929 tumor xenograft model, cemsidomide (0.1 mg/kg/day; for 21 days) promotes tumor regression (95% tumor growth suppression at 7 days) [2].

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In xenograft mouse models, oral administration of cemsidomide (1 mg/kg) for 21 days resulted in a 75% reduction in tumor volume. In a Phase 1 clinical trial involving heavily pre-treated relapsed/refractory multiple myeloma patients, cemsidomide in combination with dexamethasone achieved an overall response rate of 22% (including 1 stringent complete response, 1 very good partial response, and 5 partial responses) across all dose levels, with a clinical benefit rate of 38%.

Biochemical CRBN Binding Assay: The binding affinity of CFT7455 to cereblon (CRBN) was determined using a biochemical binding assay. Compared to pomalidomide, CFT7455 demonstrated an 800-fold improvement in CRBN binding [2].

Cellular NanoBRET Assay: The cellular binding of CFT7455 to CRBN was assessed using a NanoBRET assay. Compared to pomalidomide, CFT7455 demonstrated a 1,600-fold improvement in CRBN binding in this cellular context [2].
HiBiT-Tagged IKZF1 Degradation Assay: H929 multiple myeloma cells expressing HiBiT-tagged IKZF1 were treated with CFT7455. The degradation of IKZF1 was measured, showing that the compound induced over 75% degradation within 1.5 hours [2].
Antiproliferative Activity Assay: The antiproliferative activity of CFT7455 was evaluated across a panel of multiple myeloma cell lines, including H929 cells that had developed resistance to immunomodulatory drugs. Potent activity was observed in these assays [2].

RPMI-8226 Xenograft Model: Mice bearing RPMI-8226 tumor xenografts were used. CFT7455 was administered at doses ranging from 0.003 to 0.1 mg/kg/day. Pomalidomide was administered at 3 mg/kg/day as a comparator. In a separate arm, animals initially treated with pomalidomide were switched to CFT7455 (0.1 mg/kg/day) on day 18 [2].
H929 Xenograft Model: Mice bearing H929 tumor xenografts were treated with CFT7455 at 0.1 mg/kg/day. Dosing was discontinued after 21 days [2].
MM1.S Systemic Tumor Model: The activity of CFT7455 was also evaluated in the aggressive MM1.S systemic multiple myeloma model [2].
Combination Study: In mice bearing RPMI-8226 xenografts, the combination of CFT7455 (administered once daily, QD) and dexamethasone (administered once weekly, QW) was evaluated for efficacy and survival improvement [2].

Cemsidomide is administered orally and exhibits dose-proportional increases in systemic exposure. The molecular formula is C28H27N3O4, with a molecular weight of 469.53 g/mol. It has a predicted logP of 2.86 and a pKa (strongest basic) of 7.01. The compound is characterized by high cereblon binding affinity, enabling rapid, deep, and durable degradation of its target proteins IKZF1 and IKZF3

The most frequently observed treatment-emergent adverse events (TEAEs) are hematologic in nature. Grade 3-4 adverse events occurring in ≥10% of patients include neutropenia (34%), anemia (28%), infections (19%), lymphopenia (16%), and thrombocytopenia (13%). No grade 3/4 fatigue, nausea, or vomiting were reported. One dose-limiting toxicity (Grade 4 neutropenia lasting >7 days) was observed. No patients experienced grade 3/4 fatigue, nausea, or vomiting. Myelosuppression has been reported as manageable.

[1]. Advantageous therapies for disorders mediated by ikaros or aiolos. WO2022032132A1.

[2]. Abstract LB007: CFT7455: A novel, IKZF1/3 degrader that demonstrates potent tumor regression in IMiD-resistant multiple myeloma (MM) xenograft models. Cancer Res (2021) 81 (13_Supplement): LB007.

Cemsidomide is an orally bioavailable modulator of the E3 ubiquitin ligase complex containing cereblon (CRL4-CRBN E3 ubiquitin ligase), which possesses potential immunomodulatory and antitumor activities. After oral administration, Cemsidomide specifically binds to cereblon (CRBN), thereby affecting the activity of the ubiquitin E3 ligase and targeting certain substrate proteins for ubiquitination. This induces the proteasome-mediated degradation of certain transcription factors, including the transcriptional repressors Ikaros (IKZF1) and Aiolos (IKZF3) in T cells. This reduces the levels of these transcription factors and modulates the activity of the immune system, including the activation of T lymphocytes. Furthermore, it leads to the downregulation of the activity of several other proteins, some of which play a crucial role in the proliferation of certain cancer cell types. CRBN is the substrate recognition component of the CRL4-CRBN E3 ubiquitin ligase complex and plays a key role in the ubiquitination of certain proteins.

C28H27N3O4

469.53

469.2

C, 71.62; H, 5.80; N, 8.95; O, 13.63

2504235-67-8

2504233-68-3

155207651

Light yellow to green yellow solid powder

2.9

1

5

5

35

819

1

O=C1[C@@H](N2C(=O)C3=C4C(C(CC5=CC=C(C=C5)CN5CCOCC5)=CC=C24)=CC=C3)CCC(=O)N1

MUKCJOOKCZSQNW-DEOSSOPVSA-N

InChI=1S/C28H27N3O4/c32-25-11-10-24(27(33)29-25)31-23-9-8-20(21-2-1-3-22(26(21)23)28(31)34)16-18-4-6-19(7-5-18)17-30-12-14-35-15-13-30/h1-9,24H,10-17H2,(H,29,32,33)/t24-/m0/s1

(3S)-3-[6-[[4-(morpholin-4-ylmethyl)phenyl]methyl]-2-oxobenzo[cd]indol-1-yl]piperidine-2,6-dione

CFT7455; Cemsidomide; 2504235-67-8; D86MF5H9WJ; CFT-7455;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~25 mg/mL (~53.24 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.32 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.32 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)