Tuesday, April 28, 2015

Drugs in Clinical Pipeline: BVD-523

BVD-523 [(S)-4-(5-chloro-2-(isopropylamino)pyridin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-2-carboxamide], is a novel targeted cytotoxic designed to inhibit ERK kinase (ERK2 IC50 less than 0.1 uM), can be used to treat cancers that harbor mutations in the Mitogen activated protein kinase (MAPK) signaling pathway, making them highly reliant on ERK for survival and growth [1, 2]. In ERK2 biochemical assays, BVD-523 has  Km(ATP) as less than 0.0003 uM. Moreover, it didn't inhibit MEK1 [Km(ATP) is greater than 10 uM]. Antiproliferative effects in A375 melanoma cell line were also detected with an IC50 value of 0.18 uM [1].

The activity of Ulixertinib is as follows:

IC50 (ERK2 enzyme assay) = less than 0.1 uM

Common Name: BVD-523
Synonyms: BVD-523; BVD-ERK; VRT-0752271; VRT-752271; VX-271; Ulixertinib
IUPAC Name: (S)-4-(5-chloro-2-(isopropylamino)pyridin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-2-carboxamide
CAS Number: 869886-67-9
Mechanism of Action: Kinase Inhibitor; Mitogen activated protein kinase 3 inhibitors; Mitogen-activated protein kinase 1 inhibitors
Indication: Various Cancers; Acute Myeloid Leukaemia; Myelodysplastic Syndromes
Development Stage: Phase I/II
Company: Vertex Pharmaceuticals/BioMed Valley Discoveries

1. Ward, R. A.; et. al. Structure-Guided Design of Highly Selective and Potent Covalent Inhibitors of ERK1/2. J Med Chem 2015, 58(11), 4790-4801.
2. Tang, Q.; et. al. Pyrrole inhibitors of ERK protein kinase, synthesis thereof and intermediates thereto. US7354939B2 (synthesis and activity)
3. ClinicalTrials.gov Phase 1/2 Study of the ERK1/2 Inhibitor BVD-523 in Patients With Acute Myelogenous Leukemia or Myelodysplastic Syndromes. NCT02296242 (retrieved 28-04-2015)
4. ClinicalTrials.gov Phase I Dose-Escalation, Safety, Pharmacokinetic and Pharmacodynamic Study of BVD-523 in Patients With Advanced Malignancies. NCT01781429 (retrieved 28-04-2015)