MK-5108

Investigational

Details

Stereochemistry	ACHIRAL
Molecular Formula	C22H21ClFN3O3S
Molecular Weight	461.937
Optical Activity	UNSPECIFIED
Defined Stereocenters	2 / 2
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

OC(=O)[C@@]3(CC1=NC(NC2=NC=CS2)=CC=C1)CC[C@@H](CC3)OC4=CC=CC(Cl)=C4F

InChI

InChIKey=LCVIRAZGMYMNNT-VVONHTQRSA-N

InChI=1S/C22H21ClFN3O3S/c23-16-4-2-5-17(19(16)24)30-15-7-9-22(10-8-15,20(28)29)13-14-3-1-6-18(26-14)27-21-25-11-12-31-21/h1-6,11-12,15H,7-10,13H2,(H,28,29)(H,25,26,27)/t15-,22-

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/26620496
Curator's Comment: description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/20053775

MK-5108 is a small molecule inhibitor of AuroraA kinase with high selectivity versus Aurora-B and C. It was tested in phase I study against advanced or refractory solid tumors both as a monotherapy or in combination with docetaxel, but this study was terminated early due to toxicities at MK-5108 doses below the anticipated PK exposure target.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Serine/threonine-protein kinase Aurora-A 37 Target ID: CHEMBL4722 Sources: https://www.ncbi.nlm.nih.gov/pubmed/20053775	Inhibitor 8297		0.064 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Advanced and/or refractory solid tumors 1 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26620496	Primary		Phase I 428	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
50.2 μM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26620496	1800 mg 1 times / day multiple, oral dose: 1800 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MK-5108 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
25 μM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26620496	1200 mg 1 times / day multiple, oral dose: 1200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MK-5108 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
28.9 μM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26620496	1500 mg 1 times / day multiple, oral dose: 1500 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MK-5108 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
4.8 μM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26620496	200 mg 1 times / day multiple, oral dose: 200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MK-5108 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
11 μM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26620496	400 mg 1 times / day multiple, oral dose: 400 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MK-5108 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
20 μM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26620496	800 mg 1 times / day multiple, oral dose: 800 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MK-5108 plasma	Homo sapiens population: UNHEALTHY age: UNKNOWN sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
324.4 nM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26620496	1800 mg 1 times / day multiple, oral dose: 1800 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MK-5108 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
115.9 μM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26620496	1200 mg 1 times / day multiple, oral dose: 1200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MK-5108 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
130.7 μM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26620496	1500 mg 1 times / day multiple, oral dose: 1500 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MK-5108 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
31.2 μM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26620496	200 mg 1 times / day multiple, oral dose: 200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MK-5108 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
75.7 μM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26620496	400 mg 1 times / day multiple, oral dose: 400 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MK-5108 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
95.5 μM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26620496	800 mg 1 times / day multiple, oral dose: 800 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MK-5108 plasma	Homo sapiens population: UNHEALTHY age: UNKNOWN sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Analyte	Population
6.6 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26620496	1800 mg 1 times / day multiple, oral dose: 1800 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MK-5108 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
8.3 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26620496	1200 mg 1 times / day multiple, oral dose: 1200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MK-5108 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
11.4 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26620496	1500 mg 1 times / day multiple, oral dose: 1500 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MK-5108 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
9.3 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26620496	200 mg 1 times / day multiple, oral dose: 200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MK-5108 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
8.7 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26620496	400 mg 1 times / day multiple, oral dose: 400 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MK-5108 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
11.1 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26620496	800 mg 1 times / day multiple, oral dose: 800 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MK-5108 plasma	Homo sapiens population: UNHEALTHY age: UNKNOWN sex: FEMALE / MALE food status: UNKNOWN

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587	inhibitor 1767	inhibitor 1852

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1461

Drug as perpetrator

Target	Modality	Activity
P-gp 1650	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1346987#sid=174006374	inconclusive [IC50 0.1663 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645840#sid=363679153	no
CYP3A4 1925	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645841#sid=363679153	yes [IC50 3.7908 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645842#sid=363679153	yes [IC50 7.5637 uM]

Sourcing

Vendor/Aggregator	ID	URL
1PlusChem LLC	1P008TYT	https://www.1pchem.com/search?query=1P008TYT
MolPort	MolPort-044-193-759	https://www.molport.com/shop/molecule-link/MolPort-044-193-759
Molcore	MC34037	http://www.molcore.com/CatMC34037.html
MuseChem	I000114	https://www.musechem.com/product/I000114.html
Synthonix	SL101152	http://www.synthon-lab.com/search.php?cas_or_id=SL101152&cas_id_field=1
TargetMol	T6068	https://www.targetmol.com/search?keyword=T6068
eMolecules	275053117	https://orderbb.emolecules.com/search/#?query=275053117
eMolecules	300624290	https://orderbb.emolecules.com/search/#?query=300624290

PubMed

Title	Date	PubMed
MK-5108, a highly selective Aurora-A kinase inhibitor, shows antitumor activity alone and in combination with docetaxel.	2010 Jan	20053775
A phase I study of MK-5108, an oral aurora a kinase inhibitor, administered both as monotherapy and in combination with docetaxel, in patients with advanced or refractory solid tumors.	2016 Feb	26620496

Patents

Sample Use Guides

In Vivo Use Guide

In a randomized phase I study of against advanced or refractory solid tumors MK-5108 was administered p.o. BID Q12h on days 1-2 in 14-21 day cycles either alone (200 to 1800 mg) or in combination (100 to 225 mg) with IV docetaxel 60 mg/m(2).

Route of Administration: Oral

In Vitro Use Guide

Recombinant His-tagged human Aurora-A protein was expressed in Escherichia coli and was purified with HisTrap HP column (GE Healthcare). The Aurora-A assay reaction was conducted in the presence of 20 μmol/L ATP, 25 μmol/L Tetra-Kemptide [RRR(GLRRASLG)4R-NH2], 1.0 μCi per well [gamma-33P]-ATP, 0.1 ng per well Aurora-A in 50 mmol/L Tris-HCl (pH 7.4), 15 mmol/L Mg(OAc)2, and 0.2 mmol/L EDTA at 30°C for 40 min. To investigate the inhibition mode of MK-5108 for Aurora-A, the IC50 values of MK-5108 were determined in the presence of different concentrations of ATP. Then, the IC50 value was plotted as a function of ATP concentration to analyze the effect of ATP concentration on the IC50 value of MK-5108.

Name

Type

Language

MK-5108

Common Name

English

MK 5108

Code

English

VX-689

Code

English

CYCLOHEXANECARBOXYLIC ACID, 4-(3-CHLORO-2-FLUOROPHENOXY)-1-((6-(2-THIAZOLYLAMINO)-2-PYRIDINYL)METHYL)-, TRANS-

Common Name

English

MK5108

Code

English

Code System Code Type Description

EPA CompTox

DTXSID901026054