Replies to post #102678 on Biotech Values

[jq1234]

Nexavar inhibits the BRAF kinase, as well as other kinases. Is the new drug (PLX4032) a kinase inhibitor?

Yes, PLX4032 is a very selective BRAF kinase inhibitor. Nexavar is mutiple kinase inhibitor including BRAF, which is why it has showed some activity in melanoma. PLX stated that in the past most BRAF inhibitors were not selective enough, too much off-target toxicity, thus couldn't reach high enough dose level to sufficiently inhibit the target.

[drbio45]

I am not an expert on the drug, I just know the data looked great and it is targeted to braf.

just because a drug targets a protein doesn't mean they all work the same way or are effective. this drug worked, I don't know why it worked better than nexavar

[biomaven0]

PLX4032 does not inhibit normal (wild type) BRAF. It only inhibits mutated BRAF.

About 2/3 of melanomas have mutated BRAF (which activates ERK). But the Plexxikon drug only hits some of the mutations - seems like between 1/3 and 1/2.

Here's an abstract claiming that Nexavar in melanoma works in a manner independent of BRAF:

Sci Transl Med. 2010 Jun 9;2(35):35ra41.
Gatekeeper Mutations Mediate Resistance to BRAF-Targeted Therapies.

Whittaker S, Kirk R, Hayward R, Zambon A, Viros A, Cantarino N, Affolter A, Nourry A, Niculescu-Duvaz D, Springer C, Marais R.

Institute of Cancer Research, London, UK.

Abstract

BRAF is a serine-threonine-specific protein kinase that is mutated in 2% of human cancers. Oncogenic BRAF is a validated therapeutic target that constitutively activates mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) signaling, driving tumor cell proliferation and survival. Drugs designed to target BRAF have been developed, but it is difficult to prove that they mediate their antitumor effects by inhibiting BRAF rather than by working through off-target effects. We generated drug-resistant versions of oncogenic BRAF by mutating the gatekeeper residue. Signaling by the mutant proteins was resistant to the small-molecule inhibitor sorafenib, but sorafenib still inhibited the growth of tumors driven by the mutant protein. In contrast, both BRAF signaling and tumor growth were resistant to another RAF drug, PLX4720. These data provide unequivocal evidence that sorafenib mediates its antitumor effects in a manner that is independent of its ability to target oncogenic BRAF, whereas PLX4720 inhibits tumor growth by targeting oncogenic BRAF directly.