MKC-1

Investigational

Details

Stereochemistry	ACHIRAL
Molecular Formula	C22H16N4O4
Molecular Weight	400.3868
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

CN1C=C(C2=CC=C(C=C12)[N+]([O-])=O)C3=C(C(=O)NC3=O)C4=CN(C)C5=C4C=CC=C5

InChI

InChIKey=OVSKGTONMLKNPZ-UHFFFAOYSA-N

InChI=1S/C22H16N4O4/c1-24-10-15(13-5-3-4-6-17(13)24)19-20(22(28)23-21(19)27)16-11-25(2)18-9-12(26(29)30)7-8-14(16)18/h3-11H,1-2H3,(H,23,27,28)

HIDE SMILES / InChI

Description

MKC-1 is an orally available cell cycle inhibitor with downstream targets that include tubulin and the importin-β family. MKC-1 has shown broad antitumor activity in preclinical models. MKC-1 and its metabolites inhibit tubulin polymerization, blocking the formation of the mitotic spindle, which may result in cell cycle arrest at the G2/M phase and apoptosis. In addition, this agent has been shown to inhibit the activities of the oncogenic kinase Akt, the mTOR pathway, and importin-beta, a protein essential to the transport of other proteins from the cytosol into the nucleus. MKC-1 had been in phase II clinical trials for the treatment of ovarian cancer, endometrial cancer, pancreatic cancer and breast cancer. This compound was originally discovered by Roche, then licensed to EntreMed (now CASI Pharmaceuticals) the exclusive worldwide rights to develop and commercialize. However, no recent development has been reported.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Fibroblast growth factor receptor 6	Inhibitor 8,297
Platelet-derived growth factor receptor 6	Inhibitor 8,297
SRC 5	Inhibitor 8,297
Tyrosine-protein kinase receptor FLT3 43	Inhibitor 8,297
Protein kinase C gamma 6	Inhibitor 8,297	1.1 µM [IC50]
Tubulin 69	Inhibitor 8,297
mTOR signaling pathway 7	Inhibitor 8,297

Conditions

Condition	Modality	Highest Phase	Product
Breast cancer 434	Primary	Phase II 1,132	Unknown
Pancreatic cancer 97	Primary	Phase II 1,132	Unknown
Ovarian cancer 157	Primary	Phase II 1,132	Unknown
Endometrial cancer 43	Primary	Phase II 1,132	Unknown
Non-small cell lung cancer 206	Primary	Phase II 1,132	Unknown
Colorectal cancer 101	Primary	Phase II 1,132	Unknown

C_max

Value	Dose	Analyte	Population
1.8 μg/mL	560 mg/m² 1 times / day multiple, oral	MKC-1 plasma	Homo sapiens
1.5 μg/mL	280 mg/m² 2 times / day multiple, oral	MKC-1 plasma	Homo sapiens
1.3 μg/mL	800 mg/m² 1 times / day multiple, oral	MKC-1 plasma	Homo sapiens
2.6 μg/mL	400 mg/m² 2 times / day multiple, oral	MKC-1 plasma	Homo sapiens
0.6 μg/mL	280 mg/m² 2 times / day multiple, oral	RO 27-0431 plasma	Homo sapiens
1.2 μg/mL	280 mg/m² 2 times / day multiple, oral	RO 27-4006 plasma	Homo sapiens
1.5 μg/mL	400 mg/m² 2 times / day multiple, oral	RO 27-4006 plasma	Homo sapiens
1.2 μg/mL	800 mg/m² 1 times / day multiple, oral	RO 27-4006 plasma	Homo sapiens
1.4 μg/mL	560 mg/m² 1 times / day multiple, oral	RO 27-4006 plasma	Homo sapiens
0.9 μg/mL	400 mg/m² 2 times / day multiple, oral	RO 27-0431 plasma	Homo sapiens
0.7 μg/mL	800 mg/m² 1 times / day multiple, oral	RO 27-0431 plasma	Homo sapiens
0.4 μg/mL	560 mg/m² 1 times / day multiple, oral	RO 27-0431 plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
21.1 μg × h/mL	560 mg/m² 1 times / day multiple, oral	MKC-1 plasma	Homo sapiens
11.8 μg × h/mL	280 mg/m² 2 times / day multiple, oral	MKC-1 plasma	Homo sapiens
16.1 μg × h/mL	800 mg/m² 1 times / day multiple, oral	MKC-1 plasma	Homo sapiens
19.3 μg × h/mL	400 mg/m² 2 times / day multiple, oral	MKC-1 plasma	Homo sapiens
5.2 μg × h/mL	280 mg/m² 2 times / day multiple, oral	RO 27-0431 plasma	Homo sapiens
10.7 μg × h/mL	280 mg/m² 2 times / day multiple, oral	RO 27-4006 plasma	Homo sapiens
11.9 μg × h/mL	400 mg/m² 2 times / day multiple, oral	RO 27-4006 plasma	Homo sapiens
16.6 μg × h/mL	800 mg/m² 1 times / day multiple, oral	RO 27-4006 plasma	Homo sapiens
17.5 μg × h/mL	560 mg/m² 1 times / day multiple, oral	RO 27-4006 plasma	Homo sapiens
7.9 μg × h/mL	400 mg/m² 2 times / day multiple, oral	RO 27-0431 plasma	Homo sapiens
8.5 μg × h/mL	800 mg/m² 1 times / day multiple, oral	RO 27-0431 plasma	Homo sapiens
8.7 μg × h/mL	560 mg/m² 1 times / day multiple, oral	RO 27-0431 plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
9.2 h	560 mg/m² 1 times / day multiple, oral	MKC-1 plasma	Homo sapiens
17.6 h	280 mg/m² 2 times / day multiple, oral	MKC-1 plasma	Homo sapiens
12.5 h	800 mg/m² 1 times / day multiple, oral	MKC-1 plasma	Homo sapiens
23.1 h	400 mg/m² 2 times / day multiple, oral	MKC-1 plasma	Homo sapiens
24.5 h	280 mg/m² 2 times / day multiple, oral	RO 27-0431 plasma	Homo sapiens
15.8 h	280 mg/m² 2 times / day multiple, oral	RO 27-4006 plasma	Homo sapiens
13.8 h	400 mg/m² 2 times / day multiple, oral	RO 27-4006 plasma	Homo sapiens
13.1 h	800 mg/m² 1 times / day multiple, oral	RO 27-4006 plasma	Homo sapiens
8.8 h	560 mg/m² 1 times / day multiple, oral	RO 27-4006 plasma	Homo sapiens
12 h	400 mg/m² 2 times / day multiple, oral	RO 27-0431 plasma	Homo sapiens
13.4 h	800 mg/m² 1 times / day multiple, oral	RO 27-0431 plasma	Homo sapiens
15.5 h	560 mg/m² 1 times / day multiple, oral	RO 27-0431 plasma	Homo sapiens

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,737

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer

Drug as victim

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Target	Modality	Activity	Metabolite	Clinical evidence
CYP3A4 1,737	substrate 3,367	yes

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
1PlusChem LLC	1P000NY6	https://www.1pchem.com/search?query=1P000NY6
Angene	AGN-PC-0PHZZ6	http://www.angenechemical.com/productshow/AGN-PC-0PHZZ6.html
AstaTech	A11435	http://astatechinc.com/CPSResult.php?CRNO=A11435
BLD Pharm	BD628683	http://www.bldpharm.com/search/Search.html?keyword=BD628683
BOC Sciences	125313-92-0	http://www.bocsci.com/description.asp?cas=125313-92-0

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PubMed

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Title	Date	PubMed
A phase 2 study of oral MKC-1, an inhibitor of importin-β, tubulin, and the mTOR pathway in patients with unresectable or metastatic pancreatic cancer.	2012 Aug	21800081
mTOR inhibitors in breast cancer: a systematic review.	2012 Dec	22967800
Raf kinase inhibitor protein (RKIP) blocks signal transducer and activator of transcription 3 (STAT3) activation in breast and prostate cancer.	2014	24658061

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Patents

Sample Use Guides

In Vivo Use Guide

Cancer: MKC-1 was administered orally, twice daily, initially at 100 mg/m(2) dosing for 14 consecutive days of a 28-day cycle. This schedule was modified during the trial to fixed and continuous dosing of 150 mg per day.

Route of Administration: Oral

In Vitro Use Guide

The antiproliferative activity of MKC-1 was examined against a panel of hematopoietic cell lines including HL-60, U937, MV4;11, THP-1, Jurkat, and OCI-AML 1-5. MKC-1 showed potent and dose-dependent activity towards these cell lines, with IC50 values in the range of 20 - 400 nM.

Show entries

Name

Type

Language

MKC-1

Common Name

English

1H-PYRROLE-2,5-DIONE, 3-(1-METHYL-1H-INDOL-3-YL)-4-(1-METHYL-6-NITRO-1H-INDOL-3-YL)-

Systematic Name

English

RO-31-7453

Code

English

RO 31-7453

Code

English

MKC 1 [WHO-DD]

Common Name

English

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Classification Tree

Code System

Code

Antimitotic Agent

NCI_THESAURUS

C25974

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Code System

Code

Type

Description

NCI_THESAURUS

C2507

PRIMARY

PUBCHEM

5327686

PRIMARY

CAS

125313-92-0

PRIMARY

EPA CompTox

DTXSID60154735

PRIMARY

FDA UNII

DNZ11VPY7Q

PRIMARY

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SUBSTANCE RECORD


					DNZ11VPY7Q

MKC-1

SMILES

InChI

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Overview

OverviewOther

Drug as victim

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2