ChEMBL Resources

The SARfaris: GPCR, Kinase, ADME

Friday, 21 June 2013

New Drug Approvals 2013 - Pt. X - Trametinib (Mekinist®)

ATC code:L01XE15

On May 29th 2013, the FDA approved trametinib (Mekinist®) for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, and who have not received prior BRAF inhibitor treatment. Trametinib inhibits mutant BRAF signalling through the inhibition of a downstream kinase, MEK. In clinical trials trametinib improved the progression-free survival (PFS) from 1.5 months on standard of care chemotherapy to 4.8 months on trametinib.

Trametinib is the first approved targeted MEK inhibitor. It inhibits the kinase catalytic activity of its targets, mitogen-activated extracellular signal regulated kinase 1 and 2 ( MAP2K1 AKA MEK1, Uniprot:Q02750) and MAP2K2 AKA MEK2, Uniprot:P36507).

The sequences of the targets are here:

>sp|Q02750|MP2K1_HUMAN Dual specificity mitogen-activated protein kinase kinase 1 OS=Homo sapiens GN=MAP2K1 PE=1 SV=2

>sp|P36507|MP2K2_HUMAN Dual specificity mitogen-activated protein kinase kinase 2 OS=Homo sapiens GN=MAP2K2 PE=1 SV=1

Trametinib is administered as tablets containing trametinib dimethyl sulfoxide, the molecular formula C26H23FIN5O4 . C2H6OS with a molecular mass of 693.53. The molecular weight of trametinib itself is 615.4 and its AlogP is 3.18. Trametinib is 97.4% bound to human plasma proteins. The apparent volume of distribution (Vc/F) is 214 L. Tmax occurs 1.5 hours after dosing, and mean oral bioavailavility is 72%. Trametinib is primarily metabolised by deamidation and subsequent clearance with a half life of 3.9 to 4.8 days, clearance is 4.9 L/hr. Trametinib is not an inhibitor or substrate for CYP or PGP systems, but is an inducer of CYP3A4 activity.

Standard dose is 2mg once daily, with lower doses recommended if side effects are observed. Significant, use limiting side effects are seen in many patients.

Mekinist is produced by GSK

The Prescribing Information is here.

Thursday, 20 June 2013

Paper: The Open Access Malaria Box: A Drug Discovery Catalyst for Neglected Diseases

Historically, one of the key problems in neglected disease drug discovery has been identifying new and interesting chemotypes. Phenotypic screening of the malaria parasite, Plasmodium falciparum has yielded almost 30,000 submicromolar hits in recent years. To make this collection more accessible, a collection of 400 chemotypes has been assembled, termed the Malaria Box. Half of these compounds were selected based on their drug-like properties and the others as molecular probes. These can now be requested as a pharmacological test set by malaria biologists, but importantly by groups working on related parasites, as part of a program to make both data and compounds readily available. In this paper, the analysis and selection methodology and characteristics of the compounds are described.

Data from studies involving the Malaria Box will be in ChEMBL and the ChEMBL Malaria portal.

%A T. Spangenberg
%A J.N. Burrows
%A P. Kowalczyk
%A S. McDonald
%A TNC Wells
%D 2013
%T The Open Access Malaria Box: A Drug Discovery Catalyst for Neglected Diseases
%V 8
%P e62906
%O doi:10.1371/journal.pone.0062906

Tuesday, 4 June 2013

New Drug Approvals 2013 - Pt. IX - Dabrafenib mesylate (Tafinlar®)

ATC code: L01XE15
Wikipedia: Dabrafenib

On May 29th 2013 the FDA approved dabrafenib mesylate (trade name: Tafinlar®, research codes GSK-2118436A and GSK-2118436B) for the treatment of patients with unresectable metastatic melanoma harbouring the BRAF V600E mutation. In clinical trials, dabrafenib showed improved progression-free survival (PFS) over the comparator dacarbazine (median PFS 5.1 months for dabrafenib compared to 2.7 months for dacarbazine). Moreover, in a multicentre open-label Phase II trial dabrafenib showed effectiveness on brain metastases of melanoma regardless of whether the patients had been previously treated.

As with the previously approved BRAF inhibitor, vemurafenib, the major side effect of dabrafenib is the emergence of malignant cutaneous squamous cell carcinomas and keratoacanthomas.

The main molecular target for dabrafenib is the human mutant serine/threonine kinase, BRAF (Uniprot for wild type protein: P15056). Dabrafenib potently inhibits multiple mutant BRAF species including V600E at 0.65 nM, V600K at 0.5 nM and V600D at 1.84 nM. It also inhibits wild type BRAF at 3.2 nM and wild type CRAF at 5 nM.

Dabrafenib is administered orally as capsules containing the dabrafenib mesylate salt. Dabrafenib freebase (ChEMBL:CHEMBL2028663) has a molecular weight of 519.6 and AlogP of 5.38. The molecular formula of dabrafenib is C23H20F3N5O2S2. After oral administration, the median time to reach peak plasma concentration (Tmax) is 2 hours; the mean absolute bioavailability is 95% and the mean terminal half-life is 8 hours after oral administration.

Tafinlar® is produced by Glaxosmithkline

The full Prescribing Information is here


Saturday, 1 June 2013

Meeting: Computational Electrostatics for Biological Applications (CEBA)

Computational Electrostatics for Biological Applications (CEBA) is an international meeting joining researchers in computational disciplines aiming at discussing and exploring different approaches to improve the electrostatics calculations in the Molecular Biology field. The scope of the meeting is quite broad. However, a special focus on theoretical, numerical and modeling aspects of the Poisson-Boltzmann equation and its applications to the NanoBiotechnology field will be given.

The conference website is here