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Sendegobresib (CFT8634) is a BRD9-targeting PROTAC degrader with anticancer activity. Extracted from WO2021178920A1. May be used for synovial sarcoma and SMARCB1-deleted solid tumors
Sendegobresib (CFT8634) is an orally bioavailable heterobifunctional protein degrader targeting bromodomain-containing protein 9 (BRD9), with potential antineoplastic activity. Sendegobresib is comprised of an E3 ligase-binding moiety and a BRD9-binding moiety. Upon oral administration, sendegobresib targets and binds to BRD9 via its BRD9-binding moiety. Following BRD9 binding, the E3 ligase-binding moiety engages cereblon (CRBN), a component of the CRL4-CRBN E3 ubiquitin ligase complex, leading to ubiquitination and subsequent proteasome-mediated degradation of BRD9. This results in the inhibition of tumor cell growth in cancers that are dependent on BRD9 for survival. BRD9 is a component of one form of the Brg/Brahma-Associated Factor (BAF) complex and is required for the survival of certain cancer cells harboring specific mutations. [2, 3, 4]| 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 |
Sendegobresib is an orally bioavailable heterobifunctional protein degrader that degrades bromodomain protein 9 (BRD9; sarcoma antigen NY-SAR-29; rhabdomyosarcoma antigen MU-RMS-40.8), exhibiting potential antitumor activity. Sendegobresib consists of an E3 ubiquitin ligase-binding moiety and a BRD9-binding moiety. After oral administration, Sendegobresib targets and binds to BRD9 via its BRD9-binding moiety. Following BRD9 binding, the E3 ubiquitin ligase-binding moiety binds to cereblon (CRBN), a component of the CRL4-CRBN E3 ubiquitin ligase complex, which directs protein degradation, ultimately leading to the proteasome degradation of BRD9. This inhibits the growth of BRD9-dependent tumor cells. BRD9 is a component of the Brag/Brahma-associated factor (BAF) complex, and due to mutations, some cancer cells require BRD9 for survival.
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| Molecular Formula |
C37H45F3N6O5
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|---|---|
| Molecular Weight |
710.785619497299
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| Exact Mass |
710.34
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| Elemental Analysis |
C, 74.66; H, 6.82; N, 9.67; O, 8.84
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| CAS # |
2704617-96-7
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| Related CAS # |
(S,R)-CFT8634;2704617-95-6
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| PubChem CID |
163203607
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| Appearance |
Light green to green solid powder
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| Density |
1.36±0.1 g/cm3(Predicted)
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| Boiling Point |
856.9±65.0 °C(Predicted)
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| LogP |
3.4
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
12
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
51
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| Complexity |
1360
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| Defined Atom Stereocenter Count |
2
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| SMILES |
CC1=C(C(=O)N(C=C1C2=CC(=C(C(=C2)OC)CN3CC[C@@H](C(C3)(F)F)N4CCN(CC4)C5=C(C=C(C=C5)N[C@H]6CCC(=O)NC6=O)F)OC)C)C
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| InChi Key |
GNRGNRCQXHMQQV-ZQAZVOLISA-N
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| 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-/m0/s1
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| Chemical Name |
(3S)-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
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| Synonyms |
CFT8634; CFT 8634; CFT-8634; 2704617-96-7; AW8PEP3VZ3; 2,6-Piperidinedione, 3-((4-(4-((4S)-1-((4-(1,6-dihydro-1,4,5-trimethyl-6-oxo-3-pyridinyl)-2,6-dimethoxyphenyl)methyl)-3,3-difluoro-4-piperidinyl)-1-piperazinyl)-3-fluorophenyl)amino)-, (3S)-;
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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 Note: (1). This product requires protection from light (avoid light exposure) during transportation and storage. (2). Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| 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) |
DMSO : ~100 mg/mL (~140.69 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (3.52 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (3.52 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (3.52 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.4069 mL | 7.0344 mL | 14.0689 mL | |
| 5 mM | 0.2814 mL | 1.4069 mL | 2.8138 mL | |
| 10 mM | 0.1407 mL | 0.7034 mL | 1.4069 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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