AZ 628

• CAT Number: I005287
• CAS Number: 878739-06-1
• Molecular Formula: C₂₇H₂₅N₅O₂
• Molecular Weight: 451.53
• Purity: ≥95%
• Target: Raf
• Solubility: DMSO ≥88mg/mL Water <1.2mg/mL Ethanol <1.2mg/mL
• Storage: Desiccate at +4C
• IC50: 105 nM/34 nM/29 nM (BRAF/BRAFV600E/c-Raf-1)
• InChI: InChI=1S/C27H25N5O2/c1-17-8-9-21(31-25(33)18-6-5-7-19(12-18)27(2,3)15-28)14-24(17)30-20-10-11-23-22(13-20)26(34)32(4)16-29-23/h5-14,16,30H,1-4H3,(H,31,33)
• InChIKey: ZGBGPEDJXCYQPH-UHFFFAOYSA-N
• SMILES: CC1=C(C=C(C=C1)NC(=O)C2=CC(=CC=C2)C(C)(C)C#N)NC3=CC4=C(C=C3)N=CN(C4=O)C

AZ 628 (CAT: I005287) is a potent inhibitor that targets multiple proteins involved in the MAPK signaling pathway, particularly BRAF, BRAFV600E, and c-Raf-1. It exhibits strong inhibitory activity against these kinases, with IC50 values of 105 nM, 34 nM, and 29 nM, respectively. In addition, AZ 628 also shows inhibitory effects on other proteins such as VEGFR2, DDR2, Lyn, Flt1, and FMS. Through its action on these targets, AZ 628 effectively suppresses the growth of cancer cells, induces cell cycle arrest, and promotes apoptosis in colon and melanoma cell lines carrying the B-Raf V600E mutation. Moreover, its cross-reactivity profile suggests potential antiangiogenic properties by preventing VEGFR2 activation, similar to the mechanism observed with sorafenib.

Reference

1. Cancer Discov. 2013 Mar;3(3):350-62. doi: 10.1158/2159-8290.CD-12-0470. Epub 2013
Jan 3.

A genome-scale RNA interference screen implicates NF1 loss in resistance to RAF
inhibition.

Whittaker SR(1), Theurillat JP, Van Allen E, Wagle N, Hsiao J, Cowley GS,
Schadendorf D, Root DE, Garraway LA.

Author information:
(1)Department of Medical Oncology, Dana-Farber Cancer Institute, Boston,
Massachusetts 02215, USA.

Comment in
Cancer Discov. 2013 Mar;3(3):260-3.

RAF inhibitors such as vemurafenib and dabrafenib block BRAF-mediated cell
proliferation and achieve meaningful clinical benefit in the vast majority of
patients with BRAF(V600E)-mutant melanoma. However, some patients do not respond
to this regimen, and nearly all progress to therapeutic resistance. We used a
pooled RNA interference screen targeting more than 16,500 genes to discover
loss-of-function events that could drive resistance to RAF inhibition. The
highest ranking gene was NF1, which encodes neurofibromin, a tumor suppressor
that inhibits RAS activity. NF1 loss mediates resistance to RAF and
mitogen-activated protein kinase (MAPK) kinase kinase (MEK) inhibitors through
sustained MAPK pathway activation. However, cells lacking NF1 retained
sensitivity to the irreversible RAF inhibitor AZ628 and an ERK inhibitor. NF1
mutations were observed in BRAF-mutant tumor cells that are intrinsically
resistant to RAF inhibition and in melanoma tumors obtained from patients
exhibiting resistance to vemurafenib, thus showing the clinical potential for
NF1-driven resistance to RAF/MEK-targeted therapies.