AZ 304

AZ 304 is an inhibitor of B-RAF and B-RAF containing a valine-to-glutamate substitution at position 600 (B-RAF^V600E; IC₅₀s= 79 and 38 nM, respectively).¹ It is selective for B-RAF and B-RAF^V600E over MAP3K7 and C-terminal Src kinase (CSK) (IC₅₀s = 6,400 and 7,050 nM, respectively), as well as insulin-like growth factor 1 receptor (IGF-1R), EGFR, cyclin-dependent kinase 2 (Cdk2), Cdk4, JAK2, and c-Src (IC₅₀s = >10,000 nM for all), but also inhibits p38 MAPK, CSF-1 receptor tyrosine kinase (FMS), and C-RAF (IC₅₀s = 6, 35, and 79 nM, respectively). AZ 304 (10 and 100 µM) reduces the proliferation of RKO, HT-29, DiFi, and Caco-2 colon cancer cells. In vivo, AZ 304 (10 mg/kg twice daily), alone or in combination with the anti-EGFR antibody cetuximab, reduces tumor volume in RKO and Caco-2 colon cancer mouse xenograft models.

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1. Ma, R., Xu, L., Qu, X., et al. AZ304, a novel dual BRAF inhibitor, exerts anti-tumour effects in colorectal cancer independently of BRAF genetic status. Br. J. Cancer 118(11), 1453-1463 (2018).