ADAM10 (A Disintegrin And Metalloproteinase 10); ADAM17 (A Disintegrin And Metalloproteinase 17). Aderbasib is a potent and target-specific hydroxamate-based inhibitor of ADAM10 and ADAM17, which are sheddases that regulate the tumor necrosis factor of cancer cells. By inhibiting these enzymes, Aderbasib suppresses tumor cell proliferation.

By attaching itself to the metalloprotein domain's active site, derebasib prevents metalloprotein activity. The response between ADAM17 and sE2-Fc is inhibited by Aderbasib (10-100 μM), with an increase in compound concentration equal to sE2-Fc binding. When injected at 100 μM and 1 mM to PK15 cells, Aderbasib (100-1000 μM; takes 0.5 h) demonstrated resistance to CSFV pseudovirus. antiviral outcome [2].
In vitro, Aderbasib inhibits ADAM10 and ADAM17 activity at low nanomolar concentrations. It exhibits robust antineoplastic activity in various cancer cell lines, including those from diffuse large B-cell non-Hodgkin lymphoma, HER2+ breast cancer, and gliomas. The compound suppresses tumor cell proliferation by acting on multiple receptor classes and subclasses.

In SU-pcGBM2 NSG mice xenografts, Aderbasib (i.p.; 50 mg/kg; 5 days per week beginning at week 4; 2 weeks) explodes neuroastroma growth [1]. INCB7839 has two applications.
In vivo, Aderbasib was evaluated in combination with trastuzumab for patients with HER2-positive metastatic breast cancer. Initial results indicated a promising increase in response rates; however, subsequent phases revealed limitations in overall survival benefits. The compound exhibits robust antineoplastic activity in preclinical models.

In vitro enzyme inhibition assays for Aderbasib involve measuring ADAM10 and ADAM17 activity in the presence of varying concentrations of the compound. Recombinant enzymes are incubated with fluorogenic peptide substrates corresponding to the cleavage sites of ADAM10 or ADAM17. Fluorescence is measured over time, and IC50 values are determined from dose-response curves.

Cellular assays for Aderbasib involve culturing cancer cell lines, including diffuse large B-cell non-Hodgkin lymphoma, HER2+ breast cancer, and glioma cells. Cells are treated with Aderbasib at varying concentrations (typically 0.1-1000 nM) for 24-72 hours. Cell viability is measured using MTT or other assays. ADAM10 and ADAM17 activity is assessed by measuring the shedding of their substrates, such as TNF-α or EGFR ligands.

Animal/Disease Models: NSG mice [1]
Doses: 50 mg/kg
Route of Administration: intraperitoneal (ip) injection; % DMSO, 2% Tween 80, 48% PEG300, 48% water as injection solution. 50 mg/kg; 5 days per week starting at four weeks; 2 weeks
Experimental Results: Strong inhibition of growth of orthotopic xenografts of pediatric glioblastoma.
In vivo animal studies for Aderbasib have been conducted in xenograft models of HER2+ breast cancer and other cancers. The compound is typically administered orally. Tumor growth is monitored, and tumor tissues are analyzed for ADAM10/17 activity, shedding of substrates, and markers of apoptosis and proliferation. Combination studies with trastuzumab have also been performed.

Aderbasib is orally active and has a molecular weight of 416.48 g/mol and a molecular formula of C21H28N4O5. It is soluble in DMSO and should be stored at -20°C protected from light. Detailed pharmacokinetic parameters such as half-life, bioavailability, and tissue distribution have been characterized in preclinical and clinical studies.

Aderbasib has been evaluated for safety in clinical trials. It is generally well-tolerated but may cause side effects typical of sheddase inhibitors. The compound is not approved for clinical use and its development has been discontinued. Standard laboratory safety precautions should be taken when handling the compound.

[1]. Synergistic inhibition with a dual epidermal growth factor receptor/HER-2/neu tyrosine kinase inhibitor and a disintegrin and metalloprotease inhibitor. Cancer Res. 2008 Sep 1;68(17):7083-9.

[2]. ADAM17 is an essential attachment factor for classical swine fever virus. PLoS Pathog. 2021 Mar 8;17(3):e1009393.

INCB7839 is a novel oral ADAM metalloproteinase inhibitor designed to block activation of the epidermal growth factor receptor (EGFR) pathway. It represents a potentially important new targeted therapy for breast cancer. INCB7839 has shown encouraging clinical activity in patients with previously extensively treated, refractory breast cancer. Aderbasib is an orally bioavailable inhibitor of the ADAM (integrin and metalloproteinase) family of multifunctional membrane-binding proteins with potential antitumor activity. Aderbasib inhibits the metalloproteinase "exfoliase" activity of ADAM10 and ADAM17, thereby inhibiting tumor cell proliferation. The metalloproteinase domains of ADAM cleave cell surface proteins at extracellular sites near the cell membrane, releasing or "shedding" soluble protein extracellular domains from the cell surface; the integrin domains of these multifunctional proteins interact with various components of the extracellular matrix (ECM). ADAM10 processes specific epidermal growth factor receptor (EGFR) ligands and modulates the Notch signaling pathway by cleaving Notch and its associated ligand delta-like ligand-1 (Dll-1). ADAM17 (also known as tumor necrosis factor convertase or TACE) is involved in processing tumor necrosis factor (TNF) from its membrane-bound precursor into a soluble circulating form and participates in the processing of epidermal growth factor receptor (EGFR) family ligands. Drug Indications Investigating for/treatment of breast cancer. Mechanism of Action INCB7839 is a novel oral ADAM metalloproteinase inhibitor designed to block activation of the epidermal growth factor (EGFR) pathway. Currently approved therapies targeting the EGFR pathway have shown good efficacy in metastatic disease, validating the effectiveness of these pathways as therapeutic targets; however, their efficacy may be limited because these drugs only inhibit one or two of the four HER receptor pathways. In contrast, the exfoliase inhibitor INCB7839 has the potential to inhibit the activation of all four HER receptors, thus more thoroughly suppressing these pathways.
Aderbasib (INCB007839) is a potent, orally active inhibitor of ADAM10 and ADAM17 with robust antineoplastic activity. It was developed for the treatment of HER2+ metastatic breast cancer, diffuse large B-cell non-Hodgkin lymphoma, and gliomas. The compound's development has been discontinued. It is available for research purposes only.

C21H28N4O5

416.47082

416.206

791828-58-5

16070111

White to light yellow solid powder

1.38g/cm3

1.409

2

6

4

30

668

2

COC(=O)N1CC2(CC2)C[C@@H]([C@H]1C(=O)N3CCN(CC3)C4=CC=CC=C4)C(=O)NO

DJXMSZSZEIKLQZ-IRXDYDNUSA-N

InChI=1S/C21H28N4O5/c1-30-20(28)25-14-21(7-8-21)13-16(18(26)22-29)17(25)19(27)24-11-9-23(10-12-24)15-5-3-2-4-6-15/h2-6,16-17,29H,7-14H2,1H3,(H,22,26)/t16-,17-/m0/s1

(6S,7S)-7-[(Hydroxyamino)carbonyl]-6-[(4-phenyl-1-piperazinyl)carbonyl]-5-azaspiro[2.5]octane-5-carboxylic acid methyl ester

INCB7839 INCB007839INCB 7839 INCB-007839INCB-7839 INCB 007839

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 : ~100 mg/mL (~240.11 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.00 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 (6.00 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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Solubility in Formulation 3: ≥ 2.5 mg/mL (6.00 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.

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