| Size | Price | |
|---|---|---|
| 500mg | ||
| 1g | ||
| Other Sizes |
| Targets |
Bromodomain-containing protein 9 (BRD9). CFT8634 is a bifunctional degradation activating compound (BiDACTM) degrader that induces proteasomal degradation of BRD9 by recruiting cereblon (CRBN) E3 ligase. In HSSYII cells, as measured by HiBiT assay, CFT8634 degrades BRD9 with a DC50 of 2.7 nmol/L and an Emax of 5%. [2,3]
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|---|---|
| ln Vitro |
BRD9 Degradation Potency and Selectivity: In HSSYII cells, global proteomic analysis following treatment with CFT8634 (100 nmol/L for 4 hours) revealed that BRD9 was the only protein significantly degraded among 9,013 quantified proteins. BromoScan® profiling further confirmed its high selectivity for BRD9 at 100 nmol/L, with no significant effect on BRD4, BRD7, or known CRBN neosubstrates (such as GSPT1, IKZF1, SALL4). [2]
Activity in Multiple Myeloma: CFT8634 exhibits anti-proliferative activity in a subset of multiple myeloma (MM) cell lines. Cell lines less sensitive to pomalidomide tend to be significantly more sensitive to CFT8634 single-agent treatment. [3,4] Synergy in Combination: In vitro, CFT8634 demonstrates synergy with pomalidomide in MM cell lines where CFT8634 is active as a single agent. Pharmacokinetic and pharmacodynamic analyses show that in combination, CFT8634 and pomalidomide do not interfere with each other's target degradation (BRD9 for CFT8634, IKZF1/3 for pomalidomide), despite both utilizing cereblon as the E3 ligase. [3,4] |
| ln Vivo |
Antitumor Efficacy: In a Yamato-SS cell-derived xenograft (CDX) model, CFT8634 demonstrated dose-dependent antitumor activity, with plasma and tumor exposure proportional to the administered dose. [2]
Efficacy in PDX Models: In two patient-derived xenograft (PDX) models of synovial sarcoma (SA13412 and 310), oral administration of CFT8634 (1-50 mg/kg) induced significant tumor regression. In the SA13412 model, after 89 days of treatment followed by a 51-day observation period, durable responses were observed with no tumor regrowth. [2] Efficacy in Multiple Myeloma Model: In the NCI-H929 mouse xenograft model of multiple myeloma, CFT8634 as a single agent showed antitumor activity. When combined with pomalidomide (3 mg/kg), CFT8634 demonstrated synergy at clinically relevant exposures. This model is relatively unresponsive to pomalidomide alone, suggesting the combination can sensitize otherwise recalcitrant MM tumors. [3,4] |
| Enzyme Assay |
Bromodomain Binding Specificity: The selectivity of CFT8634 for BRD9 over other bromodomain-containing proteins was assessed using BromoScan® technology. At a concentration of 100 nmol/L, CFT8634 exhibited highly selective binding for BRD9. [2]
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| Cell Assay |
HiBiT Degradation Assay: HSSYII cells expressing HiBiT-tagged BRD9 were treated with various concentrations of CFT8634. After lysis, luminescence was measured to quantify protein levels for DC50 and Emax calculations. [2]
Global Proteomic Analysis: HSSYII cells were treated with 100 nmol/L CFT8634 for 4 hours, lysed, and subjected to LC-MS/MS analysis following protein digestion to quantify protein abundance changes and assess degradation selectivity. [2] Anti-Proliferative Activity Assay: Multiple myeloma cell lines were seeded in plates and treated with various concentrations of CFT8634. Cell viability was assessed to evaluate anti-proliferative activity. [3,4] Combination Synergy Analysis: In vitro, MM cell lines were treated with CFT8634 in combination with pomalidomide, and synergy was evaluated using proliferation assays. [3,4] |
| Animal Protocol |
Efficacy Study in CDX Model: Yamato-SS cells were implanted subcutaneously in mice. When tumors reached a certain size, mice were randomized and treated orally once daily with various doses of CFT8634 (0.3-50 mg/kg). Tumor volumes were measured, and plasma and tumor samples were collected for PK analysis. [2]
Efficacy Study in PDX Models: Synovial sarcoma PDX models (SA13412, 310) were implanted subcutaneously in mice. When tumors reached a certain size, mice were randomized and treated orally once daily with CFT8634 (1-50 mg/kg). Tumor volumes were measured. In the SA13412 model, treatment was followed by a 51-day observation period to assess durability of response. [2] Efficacy Study in Multiple Myeloma Model: NCI-H929 cells were implanted subcutaneously in female NOD/SCID mice. When tumors were established, mice were randomized and treated orally once daily with CFT8634 (3 or 10 mg/kg), pomalidomide (3 mg/kg), or the combinations. Tumor volumes were measured to assess single-agent and combination efficacy. [3,4] |
| ADME/Pharmacokinetics |
Preclinical Pharmacokinetics: In the Yamato-SS cell-derived xenograft model, CFT8634 exhibited dose-proportional plasma and tumor exposure. [2]
Clinical Pharmacokinetics: In the ongoing Phase 1/2 clinical trial, CFT8634 has demonstrated dose-proportional human plasma exposure. [3,4] PK/PD Relationship: In the NCI-H929 multiple myeloma xenograft model, when combined, CFT8634 and pomalidomide did not interfere with each other's target degradation, indicating that both agents can effectively engage their targets simultaneously in vivo. [3,4] |
| Toxicity/Toxicokinetics |
Based on the available preclinical and clinical data from the provided references (CTOS 2022 presentation and ASH 2022 abstracts), no specific toxicity parameters (such as maximum tolerated dose, dose-limiting toxicities, or detailed adverse event profiles) are described for Sendegobresib (CFT8634) . The available information focuses on its mechanism of action, preclinical efficacy, and ongoing Phase 1/2 clinical trial design. The clinical trial (NCT05355753) is actively evaluating the safety and tolerability of CFT8634, with primary endpoints including the frequency and severity of adverse events and serious adverse events, as well as the incidence of dose-limiting toxicities during dose escalation. However, specific toxicity data have not been reported in these preclinical meeting abstracts. [2, 3, 4]
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| References | |
| Additional Infomation |
Background and Mechanism of Action: Synovial sarcoma is driven by the SS18-SSX fusion, and SMARCB1-null tumors result from loss of SMARCB1 function. Both genetic perturbations disrupt the canonical BAF (cBAF) complex, creating a synthetic lethal dependency on the non-canonical BAF (ncBAF) complex and its component, BRD9. CFT8634 is an orally bioavailable, selective BRD9 degrader that induces ubiquitination and proteasomal degradation of BRD9 via ternary complex formation with cereblon, leading to inhibition of tumor cell proliferation. [2]
Clinical Development: Based on its preclinical profile, CFT8634 is being evaluated in a Phase 1/2 clinical trial (NCT05355753) for patients with synovial sarcoma and SMARCB1-null tumors. Clinical data have demonstrated robust BRD9 degradation in patient tumor samples, establishing proof of mechanism. [2,3,4] Exploration of New Indications: Preclinical studies show that CFT8634 has activity in multiple myeloma (MM) cell lines and xenograft models, and demonstrates synergy with the standard-of-care agent pomalidomide, suggesting potential for further evaluation in MM. [3,4] |
| Molecular Formula |
C37H46CLF3N6O5
|
|---|---|
| Molecular Weight |
747.24
|
| Exact Mass |
710.34
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| Elemental Analysis |
C, 74.66; H, 6.82; N, 9.67; O, 8.84
|
| CAS # |
2704617-95-6
|
| Related CAS # |
CFT8634;2704617-96-7
|
| PubChem CID |
163322333
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| Appearance |
Typically exists as solid at room temperature
|
| LogP |
3.4
|
| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
12
|
| Rotatable Bond Count |
9
|
| Heavy Atom Count |
51
|
| Complexity |
1360
|
| Defined Atom Stereocenter Count |
2
|
| SMILES |
N1C(=O)CC[C@@H](NC2=CC=C(N3CCN([C@H]4CCN(CC5=C(OC)C=C(C6C(C)=C(C)C(=O)N(C)C=6)C=C5OC)CC4(F)F)CC3)C(F)=C2)C1=O
|
| InChi Key |
GNRGNRCQXHMQQV-CPBHLAHYSA-N
|
| InChi Code |
InChI=1S/C37H45F3N6O5/c1-22-23(2)36(49)43(3)19-26(22)24-16-31(50-4)27(32(17-24)51-5)20-44-11-10-33(37(39,40)21-44)46-14-12-45(13-15-46)30-8-6-25(18-28(30)38)41-29-7-9-34(47)42-35(29)48/h6,8,16-19,29,33,41H,7,9-15,20-21H2,1-5H3,(H,42,47,48)/t29-,33+/m1/s1
|
| Chemical Name |
(3R)-3-[4-[4-[(4S)-1-[[2,6-dimethoxy-4-(1,4,5-trimethyl-6-oxopyridin-3-yl)phenyl]methyl]-3,3-difluoropiperidin-4-yl]piperazin-1-yl]-3-fluoroanilino]piperidine-2,6-dione
|
| Synonyms |
2704617-95-6; (S,R)-CFT8634; BRD9 Impurity 4; orb1944485; SCHEMBL25091494;
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.3383 mL | 6.6913 mL | 13.3826 mL | |
| 5 mM | 0.2677 mL | 1.3383 mL | 2.6765 mL | |
| 10 mM | 0.1338 mL | 0.6691 mL | 1.3383 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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