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

Structure Search

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
Sources: https://www.ncbi.nlm.nih.gov/pubmed/21800081 | https://www.ncbi.nlm.nih.gov/pubmed/15240525 | https://ncit.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&ns=NCI_Thesaurus&code=C2507 | http://en.pharmacodia.com/web/drug/1_5552.html | http://www.casipharmaceuticals.com/files/enmd_corporate_april_2008.pdf

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 Target ID: CHEMBL2095217 Sources: http://www.casipharmaceuticals.com/files/enmd_corporate_april_2008.pdf	Inhibitor 8297
Platelet-derived growth factor receptor 6 Target ID: CHEMBL2095189 Sources: http://www.casipharmaceuticals.com/files/enmd_corporate_april_2008.pdf	Inhibitor 8297
SRC 5 Target ID: CHEMBL2363074 Sources: http://www.casipharmaceuticals.com/files/enmd_corporate_april_2008.pdf	Inhibitor 8297
Tyrosine-protein kinase receptor FLT3 43 Target ID: CHEMBL1974 Sources: http://www.casipharmaceuticals.com/files/enmd_corporate_april_2008.pdf	Inhibitor 8297
Protein kinase C gamma 6 Target ID: CHEMBL3604 Sources: https://www.ncbi.nlm.nih.gov/pubmed/1732526	Inhibitor 8297	1.1 µM [IC50]
Tubulin 69 Target ID: CHEMBL2095182 Sources: http://adisinsight.springer.com/drugs/800013876 \| https://www.ncbi.nlm.nih.gov/pubmed/21800081	Inhibitor 8297
mTOR signaling pathway 7 Target ID: map04150 Sources: http://adisinsight.springer.com/drugs/800013876 \| https://www.ncbi.nlm.nih.gov/pubmed/21800081	Inhibitor 8297

Conditions

Condition	Modality	Highest Phase	Product
Breast cancer 434 Sources: http://adisinsight.springer.com/drugs/800013876 https://clinicaltrials.gov/ct2/show/NCT00306631	Primary	Phase II 1132	Unknown Approved Use Unknown
Pancreatic cancer 97 Sources: http://adisinsight.springer.com/drugs/800013876 https://clinicaltrials.gov/ct2/show/NCT00568646	Primary	Phase II 1132	Unknown Approved Use Unknown
Ovarian cancer 157 Sources: http://adisinsight.springer.com/drugs/800013876 https://clinicaltrials.gov/ct2/show/NCT00607607	Primary	Phase II 1132	Unknown Approved Use Unknown
Endometrial cancer 43 Sources: http://adisinsight.springer.com/drugs/800013876 https://clinicaltrials.gov/ct2/show/NCT00607607	Primary	Phase II 1132	Unknown Approved Use Unknown
Non-small cell lung cancer 206 Sources: http://adisinsight.springer.com/drugs/800013876 https://clinicaltrials.gov/ct2/show/NCT00408226	Primary	Phase II 1132	Unknown Approved Use Unknown
Colorectal cancer 101 Sources: http://adisinsight.springer.com/drugs/800013876 https://clinicaltrials.gov/ct2/show/NCT00016250	Primary	Phase II 1132	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
1.8 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15310782	560 mg/m² 1 times / day multiple, oral dose: 560 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	MKC-1 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
1.5 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15310782	280 mg/m² 2 times / day multiple, oral dose: 280 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	MKC-1 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
1.3 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15310782	800 mg/m² 1 times / day multiple, oral dose: 800 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	MKC-1 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
2.6 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15310782	400 mg/m² 2 times / day multiple, oral dose: 400 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	MKC-1 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
0.6 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15310782	280 mg/m² 2 times / day multiple, oral dose: 280 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	RO 27-0431 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
1.2 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15310782	280 mg/m² 2 times / day multiple, oral dose: 280 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	RO 27-4006 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
1.5 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15310782	400 mg/m² 2 times / day multiple, oral dose: 400 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	RO 27-4006 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
1.2 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15310782	800 mg/m² 1 times / day multiple, oral dose: 800 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	RO 27-4006 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
1.4 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15310782	560 mg/m² 1 times / day multiple, oral dose: 560 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	RO 27-4006 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
0.9 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15310782	400 mg/m² 2 times / day multiple, oral dose: 400 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	RO 27-0431 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
0.7 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15310782	800 mg/m² 1 times / day multiple, oral dose: 800 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	RO 27-0431 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
0.4 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15310782	560 mg/m² 1 times / day multiple, oral dose: 560 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	RO 27-0431 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
21.1 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15310782	560 mg/m² 1 times / day multiple, oral dose: 560 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	MKC-1 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
11.8 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15310782	280 mg/m² 2 times / day multiple, oral dose: 280 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	MKC-1 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
16.1 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15310782	800 mg/m² 1 times / day multiple, oral dose: 800 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	MKC-1 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
19.3 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15310782	400 mg/m² 2 times / day multiple, oral dose: 400 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	MKC-1 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
5.2 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15310782	280 mg/m² 2 times / day multiple, oral dose: 280 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	RO 27-0431 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
10.7 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15310782	280 mg/m² 2 times / day multiple, oral dose: 280 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	RO 27-4006 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
11.9 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15310782	400 mg/m² 2 times / day multiple, oral dose: 400 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	RO 27-4006 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
16.6 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15310782	800 mg/m² 1 times / day multiple, oral dose: 800 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	RO 27-4006 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
17.5 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15310782	560 mg/m² 1 times / day multiple, oral dose: 560 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	RO 27-4006 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
7.9 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15310782	400 mg/m² 2 times / day multiple, oral dose: 400 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	RO 27-0431 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
8.5 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15310782	800 mg/m² 1 times / day multiple, oral dose: 800 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	RO 27-0431 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
8.7 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15310782	560 mg/m² 1 times / day multiple, oral dose: 560 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	RO 27-0431 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Analyte	Population
9.2 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15310782	560 mg/m² 1 times / day multiple, oral dose: 560 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	MKC-1 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
17.6 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15310782	280 mg/m² 2 times / day multiple, oral dose: 280 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	MKC-1 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
12.5 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15310782	800 mg/m² 1 times / day multiple, oral dose: 800 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	MKC-1 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
23.1 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15310782	400 mg/m² 2 times / day multiple, oral dose: 400 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	MKC-1 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
24.5 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15310782	280 mg/m² 2 times / day multiple, oral dose: 280 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	RO 27-0431 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
15.8 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15310782	280 mg/m² 2 times / day multiple, oral dose: 280 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	RO 27-4006 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
13.8 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15310782	400 mg/m² 2 times / day multiple, oral dose: 400 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	RO 27-4006 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
13.1 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15310782	800 mg/m² 1 times / day multiple, oral dose: 800 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	RO 27-4006 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
8.8 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15310782	560 mg/m² 1 times / day multiple, oral dose: 560 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	RO 27-4006 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
12 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15310782	400 mg/m² 2 times / day multiple, oral dose: 400 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	RO 27-0431 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
13.4 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15310782	800 mg/m² 1 times / day multiple, oral dose: 800 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	RO 27-0431 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
15.5 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15310782	560 mg/m² 1 times / day multiple, oral dose: 560 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	RO 27-0431 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
CYP3A4 1737	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/15310782/	yes

Sourcing

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
MolPort	MolPort-044-723-396	https://www.molport.com/shop/molecule-link/MolPort-044-723-396
MuseChem	M134416	https://www.musechem.com/product/M134416.html
eMolecules	89940420	https://orderbb.emolecules.com/search/#?query=89940420

PubMed

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

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.

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

Classification Tree Code System Code

NCI_THESAURUS

C25974