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

Molecular Formula	C22H21ClFN3O3S
Molecular Weight	461.937
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	2 / 2
E/Z Centers	0
Optical Activity	UNSPECIFIED

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

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.

Substance Class	Chemical Created by `admin` on `Sat Dec 16 19:32:11 GMT 2023` Edited by `admin` on `Sat Dec 16 19:32:11 GMT 2023`
Record UNII	H8J407531S
Record Status	`Validated (UNII)`
Record Version

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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