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| Targets |
Bruton’s tyrosine kinase (BTK) [1, 2].
IC₅₀: 0.69 ± 0.091 nM (for BTK kinase activity inhibition) [2]. Cereblon (CRBN) [2]. IC₅₀: 316 ± 82 nM (for competitive binding to CRBN-DDB1 complex against biotin-labelled thalidomide) [2]. DC50 unknown |
|---|---|
| ln Vitro |
BTK degradation: BGB-16673 potently degraded BTK in vitro. In human whole blood, near complete BTK degradation was achieved within 2-3 hours at sub-nanomolar unbound concentrations. In TMD-8 cells spiked with human serum, similar potent degradation was observed [2].
BTK kinase inhibition: BGB-16673 showed potent inhibition of BTK kinase activity with an IC₅₀ of 0.69 ± 0.091 nM (n=3) [2]. CRBN binding: BGB-16673 competitively bound to the CRBN-DDB1 complex against biotin-labelled thalidomide with an IC₅₀ of 316 ± 82 nM (n=3) [2]. Cell viability: BGB-16673 exhibited potent anti-proliferation activity in wild-type TMD-8 lymphoma cells, as well as in TMD-8 cell lines expressing clinically-relevant BTK mutations including C481S, T474I, and L528W, demonstrating superior activity compared to ibrutinib and pirtobrutinib [1]. Selectivity: The binding affinity of BGB-16673 to BTK (IC₅₀ 0.69 nM) is approximately 500-fold higher than its binding affinity to the E3 ligase CRBN (IC₅₀ 316 nM), which was a key design feature enabling model simplification [2]. |
| ln Vivo |
Mouse TMD-8 xenograft model: In NCG mice bearing subcutaneous TMD-8 tumors, oral administration of BGB-16673 at 6 and 20 mg/kg (clinically achievable doses) effectively inhibited tumor growth in a dose-dependent manner. At both doses, BGB-16673 showed better efficacy compared to BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib, and pirtobrutinib) at their clinically relevant doses [1].
Mouse PK/PD studies: Following oral administration in mice (single doses at 2, 6, and 20 mg/kg; and 3 mg/kg daily for 5 days), BGB-16673 induced rapid and dose-dependent BTK degradation in blood and TMD-8 tumors. After a single 20 mg/kg dose (unbound Cmax ~1.5 nM), near-complete BTK degradation was achieved in both blood and tumor. After 5 daily doses at 3 mg/kg, >90% BTK degradation was achieved in blood and >70% in tumor cells [2]. Gene expression analysis: RNA-seq of drug-treated tumors revealed that BGB-16673 induced distinct biological effects compared to BTK inhibitors. GO term enrichment analysis showed that BGB-16673 resulted in greater inhibition of cell-cycle-related genes, NFκB targets, and certain Bcl-2 family members, correlating with its superior efficacy [1]. |
| Enzyme Assay |
BTK kinase activity assay: The assay was performed using a time-resolved fluorescence resonance energy transfer (TR-FRET) method. BTK protein (aa 393-659, His-tag) was incubated with BGB-16673 for 60 minutes at room temperature. The reaction was initiated by adding ATP (47 μM) and AQ15 peptide (0.4 μM) in buffer containing 50 mM Tris pH 7.5, 10 mM MgCl₂, 2 mM MnCl₂, 0.1 mM EDTA, 0.01% BSA, 1 mM DTT, 0.005% Tween-20, and 20 mM SEB. After 60 minutes, stop/detection solution containing MAbPT66-K and Streptavidin-XL665 was added. TR-FRET signals (ex337nm, em665nm/620nm) were recorded. The IC₅₀ was derived by fitting data to a four-parameter logistic equation [2].
CRBN-DDB1 binding assay: The assay was performed using a TR-FRET method. CRBN (aa 40-442) and DDB1 (1-1140) protein complex was incubated with BGB-16673 for 60 minutes at room temperature. Biotin-labelled thalidomide (20 nM) was added, followed by detection reagents (Mab Anti-6His Eu cryptate Gold and Streptavidin-XL665). TR-FRET signals (ex337nm, em665nm/620nm) were recorded. The IC₅₀ was derived by fitting data to a four-parameter logistic equation [2]. |
| Cell Assay |
In vitro BTK degradation in whole blood: Human or mouse whole blood was incubated with BGB-16673 (0.05-12,000 nM) for 0, 1, 3, 6, or 24 hours (n=2 per time point). After treatment, cells were lysed and BTK protein was measured by ELISA [2].
In vitro BTK degradation in TMD-8 cells: TMD-8 cells were cultured in RPMI1640 with 10% FBS. Before drug treatment, medium was replaced with human or mouse serum. Cells were incubated with BGB-16673 (0.32-5000 nM) for 0, 1, 3, or 6 hours (n=3 per time point). After treatment, cells were lysed and BTK protein was measured by HTRF assay [2]. Cell viability/proliferation assay: Anti-proliferation activity was assessed in wild-type and BTK-mutant TMD-8 cell lines. Detailed protocols were not provided [1]. |
| Animal Protocol |
Mouse tumor xenograft model: Female NCG mice (6-8 weeks old) were subcutaneously implanted with 2 × 10⁵ TMD-8 tumor cells. When mean tumor volume reached ~200 mm³, mice were randomly divided into treatment groups (n=4 per treatment group per time point). BGB-16673 was formulated in 0.5% methylcellulose and administered orally (10 mL/kg body weight). For single-dose studies, doses of 2, 6, and 20 mg/kg were administered. For repeated dosing, 3 mg/kg was administered daily for 5 days. Blood and tumor samples were collected at various time points post-dosing (4, 8, 24, 30 h for 2 and 6 mg/kg; 4, 8, 24, 30, 48, 72, 120 h for 20 mg/kg; and 0, 4, 8, 24, 30, 48, 72, 120 h post last dose for repeated dosing) [2].
Mouse PK/PD study: Following oral administration, blood samples were collected in K₂EDTA tubes. Plasma was obtained by centrifugation (1000g for 10 minutes). Plasma BGB-16673 concentrations were determined by protein precipitation followed by LC-MS/MS. BTK protein levels in blood and tumor were measured as described above [2]. |
| ADME/Pharmacokinetics |
Plasma protein binding: BGB-16673 was highly bound to plasma proteins. Unbound fraction (fu) was 0.017% in mouse plasma and 0.095% in human plasma [2].
Blood-to-plasma ratio: The mean blood-to-plasma ratio was 0.65 in mouse blood and 0.81 in human blood, indicating a plasma partitioning preference. No concentration dependency was observed from 0.1 to 10 μM [2]. Mouse PK: Following oral administration, BGB-16673 exhibited dose-dependent exposure. At a single dose of 20 mg/kg, unbound Cmax was approximately 1.5 nM [2]. Human PK prediction: Human clearance was predicted using the Fu-corrected-intercept method. Human volume of distribution at steady state was predicted using the Oie-Tozer method. Human bioavailability and absorption rate were predicted using mean values from preclinical species [2]. |
| Toxicity/Toxicokinetics |
No specific toxicity data for BGB-16673 were described in the provided literature. However, the following safety-related information was noted:
In vitro stability: BGB-16673 was very stable in hepatocytes and liver microsomes, with >80% remaining after 4 hours in hepatocytes and >85% remaining after 1 hour in liver microsomes [2]. Drug-drug interaction potential: Because BGB-16673 is stable in hepatocytes and microsomes, the risk for CYP-mediated drug-drug interactions may be low. However, detailed CYP inhibition data were not provided [2]. |
| References |
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| Additional Infomation |
BGB-16673 is an orally available Bruton’s tyrosine kinase (BTK)-targeting chimeric degradation activation compound (CDAC) that degrades the entire BTK protein, unlike BTK inhibitors which only inhibit kinase activity [1, 2].
The compound is currently under investigation in two phase I studies (NCT05006716, NCT05294731) for B-cell malignancies, including mantle cell lymphoma (MCL) [1]. BGB-16673 can overcome on-target resistance from both covalent and non-covalent BTK inhibitors, including BTK mutations such as C481S, T474I, and L528W [1]. The binding affinity to BTK (0.69 nM) is approximately 500-fold higher than to CRBN (316 nM), which enabled simplification of the mechanistic PK/PD model [2]. In clinical studies, BGB-16673 achieved complete BTK degradation in patients' blood after 50-500 mg daily oral dosing at steady state (week 4-5). In bone marrow and lymph node tissues, significant BTK degradation was achieved at steady state (≥5 weeks). At 50 and 100 mg doses, only 10-20% remaining BTK-positive tumor cells were measured; at 200 mg, 10% to near-complete reduction was achieved [2]. The predicted human steady-state BTK degradation using the simplified PK/PD model was consistent with observed preliminary human BTK degradation data [2]. |
| Molecular Formula |
C47H54N12O4
|
|---|---|
| Molecular Weight |
851.01
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| Exact Mass |
850.439098
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| Elemental Analysis |
C, 66.33; H, 6.40; N, 19.75; O, 7.52
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| CAS # |
2736508-60-2
|
| PubChem CID |
166521972
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| Appearance |
Light yellow to green yellow solid powder
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| Density |
1.284±0.06 g/cm3(Temp: 25 °C; Press: 760 Torr)(predicted)
|
| LogP |
6.2
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| Hydrogen Bond Donor Count |
3
|
| Hydrogen Bond Acceptor Count |
12
|
| Rotatable Bond Count |
11
|
| Heavy Atom Count |
63
|
| Complexity |
1560
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C12C=C(C3=CC=C(N4CCN(CC5CCN(C6C=CC(N7CCC(=O)NC7=O)=CC=6)CC5)CC4)N=C3)NC=1N=CN=C2C1C=CC([C@@H](C)NC(=O)C2ON=C(C(C)(C)C)N=2)=C(C)C=1
|
| InChi Key |
ZSOLMVZWDSGPDD-SSEXGKCCSA-N
|
| InChi Code |
InChI=1S/C47H54N12O4/c1-29-24-32(6-12-36(29)30(2)51-43(61)44-54-45(55-63-44)47(3,4)5)41-37-25-38(52-42(37)50-28-49-41)33-7-13-39(48-26-33)58-22-20-56(21-23-58)27-31-14-17-57(18-15-31)34-8-10-35(11-9-34)59-19-16-40(60)53-46(59)62/h6-13,24-26,28,30-31H,14-23,27H2,1-5H3,(H,51,61)(H,49,50,52)(H,53,60,62)/t30-/m1/s1
|
| Chemical Name |
3-tert-butyl-N-[(1R)-1-[4-[6-[6-[4-[[1-[4-(2,4-dioxo-1,3-diazinan-1-yl)phenyl]piperidin-4-yl]methyl]piperazin-1-yl]-3-pyridinyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methylphenyl]ethyl]-1,2,4-oxadiazole-5-carboxamide
|
| Synonyms |
BTK-IN-29; BGB16673; BGB-16673; BGB 16673; Catadegbrutinib; 2736508-60-2; PF6GPZ4DYT; RefChem:1081283;
|
| 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) |
Soluble in DMSO: ~125 mg/mL (146.9 mM)
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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 | 1.1751 mL | 5.8754 mL | 11.7507 mL | |
| 5 mM | 0.2350 mL | 1.1751 mL | 2.3501 mL | |
| 10 mM | 0.1175 mL | 0.5875 mL | 1.1751 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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