MLN 2480 (Synonyms: BIIB-024, TAK-580)

MLN2480 is an potent pan-RAF kinase inhibitor.

In vitro: MLN2480 inhibits MAPK pathway signaling in BRAF mutant and some RAS mutant preclinical cancer models at concentrations that are tolerated in vivo. In vitro analysis of this drug combination of MLN2480 and TAK-733 in cell proliferation assays demonstrates synergistic activity [1].

In vivo: MLN2480 is most potent in BRAF mutant melanoma models but also has single agent activity in some RAS mutant models. The MLN2480 and TAK-733 combination inhibits the growth of a broader range of RAS mutant tumor models than MLN2480 single agent, including primary human tumor xenograft models of melanoma and CRC [2].

Clinical trial: In the first-in-human study (n=24), the safety profile of MLN2480 up to 200 mg Q2D was acceptable. Accrual continues at 200 mg to confirm the MTD [2].

References:
[1] Elizabeth Grace Carideo Cunniff, Julie Zhang, Jouhara Chouitar, et al.  Combination treatment with the investigational RAF kinase inhibitor MLN2480 and the investigational MEK kinase inhibitor TAK-733 inhibits the growth of BRAF mutant and RAS mutant preclinical models of melanoma and CRC. Mol Cancer Ther November 2013 12; C146
[2] Drew Warren Rasco, Anthony J.   Olszanski, Amita Patnaik, et al. MLN2480, an investigational oral pan-RAF kinase inhibitor, in patients (pts) with relapsed or refractory solid tumors: Phase I study. J Clin Oncol 31, 2013 (suppl; abstr 2547)