Plx-4032 (RG7024)

The Uses of Plx-4032 (RG7024)

Vemurafenib selective BRAFV600E kinase inhibitor; an antitumor agent. Vemurafenib functions by inhibiting the proliferation and mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase and ERK phosphorylation in a panel of tumor cell lines, including melanoma cell lines expressing BRAFV600E or other mutant BRAF proteins altered at codon 600. Potent B-Raf inhibitor

Definition

ChEBI: Vemurafenib is a pyrrolopyridine that is 1H-pyrrolo[2,3-b]pyridine which is substituted at position 5 by a p-chlorophenyl group and at positions 3 by a 3-amino-2,6-difluorobenzoyl group, the amino group of which has undergone formal condensation with propane-1-sulfonic acid to give the corresponding sulfonamide. An inhibitor of BRAF and other kinases. It has a role as an antineoplastic agent and a B-Raf inhibitor. It is a pyrrolopyridine, a sulfonamide, a member of monochlorobenzenes, a difluorobenzene and an aromatic ketone.

brand name

Zelboraf

General Description

Class: dual threonine/tyrosine kinase; Treatment: melanoma with BRAF mutations; Elimination half-life = 57 h; Protein binding > 99%

Pharmacokinetics

1

Pharmacokinetics

The recommended daily dose of vemurafenib is 1,920 mg (4 × 240 mg tablets, BID), the highest dosage among the three FDA-approved RAF inhibitors (Table 2). One contributing factor for such a high dose is the poor and variable oral bioavailability due to both low cell permeability and poor aqueous solubility. Nevertheless, vemurafenib is absorbed rapidly after a single oral dose of 960 mg, reaching a maximum drug concentration approximately 4 h after administration. It also exhibits long elimination half-life (57 h). It is cleared predominantly via the hepatic route. Following oral administration, the parent drug predominates in the plasma, and the isomeric monohydroxylated species 5 are the only metabolites detected in the plasma due to CYP3A4 mediated oxidation (Fig. 6).

Clinical Use

Vemurafenib was originally discovered at Plexxikon and has been co-developed by Roche and Plexxikon as an oral BRAF inhibitor for the treatment of patients with BRAFV600E mutation- positive metastatic melanoma. The drug displays good potency and selectivity for the V600E mutation (IC50 = 3.2–14 nM), an oncoprotein, over the wild-type BRAF (IC50 = 21–370 nM). The compound is less potent in in vitro kinase assays than other Plexxikon BRAF inhibitors, but it was selected for clinical development based on its enhanced potency against the BARFV600E-containing A374 melanoma cell line.

Synthesis

The synthesis described below is based on a recent process patent (the Scheme).

Commercially available 2-amino-5-bromopyridine (271) was treated with 4-chlorophenylboronic acid (272) in the presence of Na2CO3 and a catalytic amount of Pd(OAc)2/PdCl2(dppf)CH2Cl2 to give Suzuki product 273 in 83% yield. Arene 273 was subjected to iodination conditions using NIS and TFA to provide iodide 274 in 98% yield. Iodide 274 and pinacol vinylboronate 275 were coupled under Suzuki conditions followed by treatment with acid to affect a tandem coupling¨Ccyclization sequence which resulted in pyrimidyl pyrrole 276 in good yield. This material was treated with aluminum trichloride and then subjected to the the acyl chloride of commercially available sulfonamide acid 277, triggering a Friedel- Crafts reaction providing vemurafenib (XXIV) in 85% yield.

Drug interactions

Potentially hazardous interactions with other drugs
Anticoagulants: possibly enhances anticoagulant effect of warfarin.
Antipsychotics: avoid concomitant use with clozapine, risk of agranulocytosis.
Oestrogens and progestogens: contraceptive effect possibly reduced.

Metabolism

Only 5
% of a dose of vemurafenib is metabolised. 94
% of the dose is excreted in the faeces and 1
% in the urine.