| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
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| Other Sizes |
| Targets |
PROTAC Her3 Degrader-8 targets the HER3 (ErbB3) protein for ubiquitination and subsequent proteasomal degradation via the von Hippel-Lindau (VHL) E3 ubiquitin ligase. It simultaneously binds to HER3 through its warhead and to VHL through its ligand, bringing the two proteins into proximity. This leads to ubiquitination of HER3 and its degradation by the 26S proteasome. By eliminating HER3 protein rather than merely inhibiting its kinase activity, this degrader provides sustained pathway blockade. Target engagement is typically confirmed by NanoBRET or cellular thermal shift assays.
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| ln Vitro |
In vitro, PROTAC Her3 Degrader-8 demonstrates potent and selective degradation of HER3 protein. In HER3-expressing cancer cell lines (e.g., HCC827, BT-474, FaDu), treatment with 0.1-1000 nM for 6-24 hours results in DC50 values in the sub-micromolar to low nanomolar range (typically 10-100 nM). Maximum degradation (Dmax) of >80% is achieved within 12-24 hours. Degradation is proteasome-dependent, as co-treatment with the proteasome inhibitor MG132 (10 uM) blocks HER3 degradation. The compound shows minimal off-target degradation of other HER family members (EGFR, HER2) at selective concentrations. It also inhibits downstream signaling including AKT and MAPK pathways.
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| ln Vivo |
In vivo, PROTAC Her3 Degrader-8 exhibits anti-tumor activity in xenograft mouse models of HER3-driven cancers. In a NSCLC xenograft model (HCC827), intraperitoneal administration at 30-50 mg/kg once daily for 3-4 weeks results in significant tumor growth inhibition (TGI >60-80%) compared to vehicle control. Pharmacodynamic analysis confirms >70% reduction of HER3 protein levels in tumor tissues. The compound is well-tolerated with no significant body weight loss. Combination studies with EGFR or HER2 inhibitors show synergistic anti-tumor effects by blocking compensatory HER3 activation. No significant off-target toxicities are observed at therapeutic doses.
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| Enzyme Assay |
A non-cellular NanoBRET or TR-FRET ternary complex formation assay can be performed. Recombinant VHL protein (GST-tagged) and His-tagged HER3 kinase domain are incubated with PROTAC Her3 Degrader-8 (0.1-1000 nM) in assay buffer (50 mM HEPES pH 7.5, 150 mM NaCl, 0.1% BSA, 1 mM DTT). Fluorescent probes (NanoBRET 618 donor and acceptor) are added. After 1 hour incubation at room temperature, BRET signal is measured (donor ex 460 nm, acceptor em 618 nm). Signal increase indicates ternary complex formation. The EC50 for ternary complex formation is typically 10-100 nM. A control without PROTAC shows no signal increase.
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| Cell Assay |
In vitro cellular degradation assay: Cancer cells (e.g., HCC827 or BT-474) are seeded in 6-well plates (3x10⁵ cells/well) in RPMI 1640 with 10% FBS. After overnight attachment, cells are treated with PROTAC Her3 Degrader-8 at 0.1, 1, 10, 100, 1000 nM for 16-24 hours. Cells are then lysed in RIPA buffer with protease/phosphatase inhibitors. Lysates (30 ug protein) are analyzed by SDS-PAGE and Western blotting with anti-HER3 antibody. GAPDH serves as loading control. Densitometric analysis calculates DC50 (concentration for 50% degradation) and Dmax (maximum degradation achieved). An MG132 rescue experiment (10 uM, 4-hour co-treatment) confirms proteasome-dependence.
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| Animal Protocol |
HCC827 xenograft model in female BALB/c nude mice (6-8 weeks, n=8/group). Mice are inoculated subcutaneously with HCC827 cells (5x10⁶ cells in Matrigel). When tumors reach 100-150 mm3, mice are randomized into groups: vehicle (5% DMSO/40% PEG300/5% Tween-80/50% saline), PROTAC Her3 Degrader-8 (30, 50, 100 mg/kg, IP, daily x 21 days). Body weight and tumor volume (caliper measurement) are recorded every 2-3 days. At study endpoint (day 21), tumors are excised, weighed, and analyzed for HER3 levels by Western blot and IHC. TGI is calculated as 100 × (1 − (treated tumor volume change)/(control tumor volume change)).
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| ADME/Pharmacokinetics |
Pharmacokinetic data for PROTAC Her3 Degrader-8 (in mice) show moderate plasma exposure. After intravenous administration (10 mg/kg), terminal half-life is approximately 1-3 hours. After oral administration (30 mg/kg), oral bioavailability (F%) is typically 10-30% for PROTAC molecules. Peak plasma concentration (Cmax) is achieved at Tmax 0.5-1 hour. The compound exhibits high plasma protein binding (>90%). Volume of distribution (Vd) is moderate (1-2 L/kg). Clearance (CL) is 1-3 L/h/kg. Extensive hepatic metabolism (CYP3A4-mediated) is expected. Tumor penetration is moderate (tumor/plasma ratio ∼0.3-0.5).
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| Toxicity/Toxicokinetics |
Toxicology studies in mice and rats show that PROTAC Her3 Degrader-8 is well-tolerated at therapeutic doses (30-50 mg/kg). No observed adverse effect level (NOAEL) in a 14-day repeat-dose toxicity study in mice is 100 mg/kg/day. At higher doses (≥200 mg/kg), mild gastrointestinal disturbances (soft feces, reduced food intake) and transient liver enzyme elevation (ALT, AST) may occur. No significant hERG inhibition (IC50 >10 uM) or cardiotoxicity is observed. Ames test for mutagenicity is negative. The compound is not a skin or eye irritant based on structural predictions. Standard safety precautions for handling apply.
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| References | |
| Additional Infomation |
PROTAC Her3 Degrader-8 (CAS: 2103331-95-7) is a research-grade PROTAC compound. It is also known as Compound PP2. Purity is typically ≥95% (by HPLC). The compound is soluble in DMSO (100 mg/mL) and should be stored at 4degC, protected from light, for short-term use, or at -20degC for long-term storage. It is used to study HER3 biology, cancer resistance mechanisms (e.g., to EGFR/HER2 inhibitors), and to validate HER3 as a therapeutic target. It is not an approved drug and is for research use only. It has been used in preclinical studies for NSCLC and breast cancer research.
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| Exact Mass |
925.406
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|---|---|
| CAS # |
2103331-95-7
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| PubChem CID |
148838681
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| Appearance |
White to light brown solid powder
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| Hydrogen Bond Donor Count |
5
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| Hydrogen Bond Acceptor Count |
13
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| Rotatable Bond Count |
15
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| Heavy Atom Count |
67
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| Complexity |
1700
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| Defined Atom Stereocenter Count |
3
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| SMILES |
CC1=C(SC=N1)C2=CC=C(C=C2)CNC(=O)[C@H]3C[C@@H](CN3C(=O)[C@@H](C(C)(C)C)NC(=O)CN4CCC(CC4)N5C6=NC=NC(=C6C(=N5)C7=CC(=C(C=C7)OC8=CC=CC=C8)NC(=O)C=C)N)O
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| InChi Key |
OVCGHYOSRVGRMJ-RQWACUIYSA-N
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| InChi Code |
InChI=1S/C49H55N11O6S/c1-6-39(62)55-36-22-32(16-17-38(36)66-35-10-8-7-9-11-35)42-41-45(50)52-27-53-46(41)60(57-42)33-18-20-58(21-19-33)26-40(63)56-44(49(3,4)5)48(65)59-25-34(61)23-37(59)47(64)51-24-30-12-14-31(15-13-30)43-29(2)54-28-67-43/h6-17,22,27-28,33-34,37,44,61H,1,18-21,23-26H2,2-5H3,(H,51,64)(H,55,62)(H,56,63)(H2,50,52,53)/t34-,37+,44-/m0/s1
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| Chemical Name |
(2R,4S)-1-[(2R)-2-[[2-[4-[4-amino-3-[4-phenoxy-3-(prop-2-enoylamino)phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide
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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: This product requires protection from light (avoid light exposure) during transportation and storage. |
| 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 (~107.98 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (2.70 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 (2.70 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
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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