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 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.

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.

[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, orally available ADAM metalloprotease inhibitor that is designed to block activation of the epidermal growth factor (EGFR) pathways. It represents a potentially important new class of targeted breast cancer therapy. It has shown promising clinical activity in heavily pretreated, refractory breast cancer patients.
Aderbasib is an orally bioavailable inhibitor of the ADAM (A Disintegrin And Metalloprotease) family of multifunctional membrane-bound proteins with potential antineoplastic activity. Aderbasib represses the metalloproteinase 'sheddase' activities of ADAM10 and ADAM17, which may result in the inhibition of tumor cell proliferation. The metalloproteinase domains of ADAMs cleave cell surface proteins at extracellular sites proximal to the cell membrane, releasing or "shedding" soluble protein etcodomains from the cell surface; the disintegrin domains of these multifunctional proteins interact with various components of the extracellular matrix (ECM). ADAM10 processes particular epithelial growth factor receptor (EGFR) ligands and appears to regulate Notch signaling through the cleavage of Notch and its related ligand delta-like ligand-1 (Dll-1). ADAM17 (also known as Tumor necrosis factor-Converting Enzyme or TACE) is involved in processing tumor necrosis factor (TNF) from its membrane bound precursor to its soluble circulating form and in processing ligands for the epidermal growth factor receptor (EGFR) family.

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Drug Indication
Investigated for use/treatment in breast cancer.

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Mechanism of Action
INCB7839 is a novel, orally available ADAM metalloprotease inhibitor that is designed to block activation of the epidermal growth factor (EGFR) pathways. Currently approved therapies that target the EGFR pathways have shown promising efficacy in metastatic disease, validating these pathways as targets; however, efficacy may be limited due to the fact that these drugs inhibit only one or two of the four HER receptor pathways. In contrast, the sheddase inhibitor, INCB7839, has the potential to inhibit activation through all four of the HER receptors, resulting in more complete inhibition of these pathways.

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.)