Takinib

• CAT Number: I011854
• CAS Number: 1111556-37-6
• Molecular Formula: CHNO
• Molecular Weight: 322.36
• Purity: ≥95%
• Storage: 20°C
• InChI: InChI=1S/C18H18N4O2/c1-2-10-22-15-9-4-3-8-14(15)20-18(22)21-17(24)13-7-5-6-12(11-13)16(19)23/h3-9,11H,2,10H2,1H3,(H2,19,23)(H,20,21,24)
• InChIKey: UOZVVPXKJGOFIG-UHFFFAOYSA-N
• SMILES: CCCN1C2=CC=CC=C2N=C1NC(=O)C3=CC=CC(=C3)C(=O)N

Takinib (CAT: I011854) is a potent inhibitor of TAK1 (transforming growth factor-beta-activated kinase 1), targeting both autophosphorylated and non-phosphorylated forms. By binding to the ATP-binding pocket of TAK1, takinib effectively slows down the rate-limiting step of TAK1 activation. This inhibition makes takinib a promising candidate for the development of compounds that can sensitize cells to TNF-α-induced cell death. This property holds potential implications for the treatment of cancer and autoimmune diseases, as it offers a means to modulate cellular responses and enhance the effectiveness of TNF-α-based therapies.

Reference

1. Cell Chem Biol. 2017 Aug 17;24(8):1029-1039.e7. doi:
10.1016/j.chembiol.2017.07.011.

Takinib, a Selective TAK1 Inhibitor, Broadens the Therapeutic Efficacy of TNF-α
Inhibition for Cancer and Autoimmune Disease.

Totzke J(1), Gurbani D(2), Raphemot R(3), Hughes PF(1), Bodoor K(4), Carlson
DA(1), Loiselle DR(1), Bera AK(2), Eibschutz LS(1), Perkins MM(3), Eubanks AL(3),
Campbell PL(5), Fox DA(5), Westover KD(6), Haystead TAJ(7), Derbyshire ER(8).

Author information:

(1)Department of Pharmacology and Cancer Biology, Duke University, Durham, NC
27710, USA.
(2)Departments of Biochemistry and Radiation Oncology, University of Texas,
Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
(3)Department of Chemistry, Duke University, Durham, NC 27710, USA.
(4)Department of Pharmacology and Cancer Biology, Duke University, Durham, NC
27710, USA; Department of Applied Biology, Jordan University of Science and
Technology, PO Box 3030, Irbid 22110, Jordan.
(5)University of Michigan, Division of Rheumatology and Clinical Autoimmunity
Center of Excellence, Ann Arbor, MI 48109, USA.
(6)Departments of Biochemistry and Radiation Oncology, University of Texas,
Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
Electronic address: .
(7)Department of Pharmacology and Cancer Biology, Duke University, Durham, NC
27710, USA. Electronic address: .
(8)Department of Chemistry, Duke University, Durham, NC 27710, USA. Electronic
address: .

Tumor necrosis factor alpha (TNF-α) has both positive and negative roles in human
disease. In certain cancers, TNF-α is infused locally to promote tumor
regression, but dose-limiting inflammatory effects limit broader utility. In
autoimmune disease, anti-TNF-α antibodies control inflammation in most patients,
but these benefits are offset during chronic treatment. TAK1 acts as a key
mediator between survival and cell death in TNF-α-mediated signaling. Here, we
describe Takinib, a potent and selective TAK1 inhibitor that induces apoptosis
following TNF-α stimulation in cell models of rheumatoid arthritis and metastatic
breast cancer. We demonstrate that Takinib is an inhibitor of autophosphorylated
and non-phosphorylated TAK1 that binds within the ATP-binding pocket and inhibits
by slowing down the rate-limiting step of TAK1 activation. Overall, Takinib is an
attractive starting point for the development of inhibitors that sensitize cells
to TNF-α-induced cell death, with general implications for cancer and autoimmune
disease treatment.