MK-2206

Investigational

Details

Stereochemistry	ACHIRAL
Molecular Formula	C25H21N5O.ClH
Molecular Weight	443.928
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

Cl.NC1(CCC1)C2=CC=C(C=C2)C3=NC4=C(C=C3C5=CC=CC=C5)C6=NNC(=O)N6C=C4

InChI

InChIKey=LFYOZCBFOSSLNJ-UHFFFAOYSA-N

InChI=1S/C25H21N5O.ClH/c26-25(12-4-13-25)18-9-7-17(8-10-18)22-19(16-5-2-1-3-6-16)15-20-21(27-22)11-14-30-23(20)28-29-24(30)31;/h1-3,5-11,14-15H,4,12-13,26H2,(H,29,31);1H

HIDE SMILES / InChI

Molecular Formula	C25H21N5O
Molecular Weight	407.4671
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Molecular Formula	ClH
Molecular Weight	36.461
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: https://www.cancer.gov/publications/dictionaries/cancer-drug?cdrid=596332
Curator's Comment: description was created based on several sources, including: http://adisinsight.springer.com/drugs/800028810 | http://www.pharmacodia.com/yaodu/html/v1/chemicals/cddaa6e1ad5ba4c70c6c05db38099fa0.html | https://en.wikipedia.org/wiki/MK-2206 | https://www.ncbi.nlm.nih.gov/pubmed/20571069

MK-2206 is an oral selective allosteric inhibitor of Akt that targets all three isoforms of human Akt (Akt-1, Akt-2 and Akt-3). In a phase I study of solid tumors, MK-2206 demonstrated evidence of target modulation and anti-proliferative activity as a single agent and in combination with other agents. Current ongoing trials of MK-2206 include monotherapy and combination therapy in breast cancer, colorectal cancer, haematological malignancies, non-small cell lung cancer and other. Detected treatment-related adverse event are: rash, fatigue, hyperglycemia.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Serine/threonine-protein kinase AKT 29 Target ID: CHEMBL4282 Sources: https://www.ncbi.nlm.nih.gov/pubmed/20571069	Negative Allosteric Modulator 42	5.0 nM [IC50]
Serine/threonine-protein kinase AKT2 17 Target ID: CHEMBL2431 Sources: https://www.ncbi.nlm.nih.gov/pubmed/20571069	Negative Allosteric Modulator 42	12.0 nM [IC50]
Serine/threonine-protein kinase AKT3 17 Target ID: CHEMBL4816 Sources: https://www.ncbi.nlm.nih.gov/pubmed/20571069	Negative Allosteric Modulator 42	65.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Breast cancer 434 Sources: http://adisinsight.springer.com/drugs/800028810 https://clinicaltrials.gov/ct2/show/NCT01776008	Primary	Phase II 1132	Unknown Approved Use Unknown
Adenoid cystic carcinoma 6 Sources: http://meetinglibrary.asco.org/content/147103-156	Primary	Phase II 1132	Unknown Approved Use Unknown
Colorectal cancer 101 Sources: http://adisinsight.springer.com/drugs/800028810 https://www.ncbi.nlm.nih.gov/pubmed/25637165	Primary	Phase II 1132	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
264 nM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25239610	200 mg 1 times / week single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	MK-2206 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
345 nM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25239610	200 mg 1 times / week multiple, oral dose: 200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MK-2206 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
466 nM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25239610	300 mg single, oral dose: 300 mg route of administration: Oral experiment type: SINGLE co-administered:	MK-2206 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
66.4 nM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22025163	60 mg single, oral dose: 60 mg route of administration: Oral experiment type: SINGLE co-administered:	MK-2206 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
132 nM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22025163	90 mg single, oral dose: 90 mg route of administration: Oral experiment type: SINGLE co-administered:	MK-2206 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
163 nM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22025163	60 mg 1 times / 2 days multiple, oral dose: 60 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MK-2206 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
232 nM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22025163	90 mg 1 times / 2 days multiple, oral dose: 90 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MK-2206 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

AUC

Value	Dose	Analyte	Population
16400 nM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25239610	200 mg 1 times / week single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	MK-2206 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
23500 nM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25239610	200 mg 1 times / week multiple, oral dose: 200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MK-2206 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
27700 nM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25239610	300 mg single, oral dose: 300 mg route of administration: Oral experiment type: SINGLE co-administered:	MK-2206 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
1820 nM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22025163	60 mg single, oral dose: 60 mg route of administration: Oral experiment type: SINGLE co-administered:	MK-2206 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
3950 nM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22025163	90 mg single, oral dose: 90 mg route of administration: Oral experiment type: SINGLE co-administered:	MK-2206 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
5860 nM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22025163	60 mg 1 times / 2 days multiple, oral dose: 60 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MK-2206 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
7970 nM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22025163	90 mg 1 times / 2 days multiple, oral dose: 90 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MK-2206 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

T_1/2

Value	Dose	Analyte	Population
75.1 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25239610	200 mg 1 times / week multiple, oral dose: 200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MK-2206 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
71.3 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22025163	60 mg 1 times / 2 days multiple, oral dose: 60 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MK-2206 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
66.2 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22025163	90 mg 1 times / 2 days multiple, oral dose: 90 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MK-2206 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

Doses

Dose	Population	Adverse events
300 mg 1 times / week multiple, oral Highest studied dose Dose: 300 mg, 1 times / week Route: oral Route: multiple Dose: 300 mg, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/25239610 Page: p.5, 25	unhealthy, ADULT n = 3 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/25239610 Page: p.5, 25	DLT: Skin rash... Dose limiting toxicities: Skin rash (grade 3, 100%) Sources: https://pubmed.ncbi.nlm.nih.gov/25239610 Page: p.5, 25
200 mg 1 times / week multiple, oral MTD Dose: 200 mg, 1 times / week Route: oral Route: multiple Dose: 200 mg, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/25239610 Page: p.5, 25	unhealthy, ADULT n = 17 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 17 Sources: https://pubmed.ncbi.nlm.nih.gov/25239610 Page: p.5, 25	DLT: Skin rash, Dermatitis acneiform... Dose limiting toxicities: Skin rash (grade 3, 17.6%) Dermatitis acneiform (grade 3, 5.9%) Sources: https://pubmed.ncbi.nlm.nih.gov/25239610 Page: p.5, 25
60 mg 1 times / 2 days multiple, oral MTD Dose: 60 mg, 1 times / 2 days Route: oral Route: multiple Dose: 60 mg, 1 times / 2 days Sources: https://pubmed.ncbi.nlm.nih.gov/22025163 Page: p.4690	unhealthy, ADULT n = 20 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 20 Sources: https://pubmed.ncbi.nlm.nih.gov/22025163 Page: p.4690	DLT: Erythematous rash... Dose limiting toxicities: Erythematous rash (grade 3, 5%) Sources: https://pubmed.ncbi.nlm.nih.gov/22025163 Page: p.4690
60 mg 1 times / 2 days multiple, oral MTD Dose: 60 mg, 1 times / 2 days Route: oral Route: multiple Dose: 60 mg, 1 times / 2 days Sources: https://pubmed.ncbi.nlm.nih.gov/25239610 Page: sup. table1	unhealthy, ADULT n = 38 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 38 Sources: https://pubmed.ncbi.nlm.nih.gov/25239610 Page: sup. table1	DLT: Stomatitis, Skin rash... Dose limiting toxicities: Stomatitis (grade 3, 2.6%) Skin rash (grade 3, 2.6%) Skin rash (grade 3, 18.4%) Skin rash (grade 3, 5.3%) Sources: https://pubmed.ncbi.nlm.nih.gov/25239610 Page: sup. table1
90 mg 1 times / 2 days multiple, oral Studied dose Dose: 90 mg, 1 times / 2 days Route: oral Route: multiple Dose: 90 mg, 1 times / 2 days Sources: https://pubmed.ncbi.nlm.nih.gov/22025163 Page: p.4690	unhealthy, ADULT n = 7 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 7 Sources: https://pubmed.ncbi.nlm.nih.gov/22025163 Page: p.4690	DLT: Stomatitis, Erythematous rash... Dose limiting toxicities: Stomatitis (grade 3, 14.3%) Erythematous rash (grade 3-4, 57.1%) Sources: https://pubmed.ncbi.nlm.nih.gov/22025163 Page: p.4690

AEs

AE	Significance	Dose	Population
Skin rash	grade 3, 100% DLT	300 mg 1 times / week multiple, oral Highest studied dose Dose: 300 mg, 1 times / week Route: oral Route: multiple Dose: 300 mg, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/25239610 Page: p.5, 25	unhealthy, ADULT n = 3 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/25239610 Page: p.5, 25
Skin rash	grade 3, 17.6% DLT	200 mg 1 times / week multiple, oral MTD Dose: 200 mg, 1 times / week Route: oral Route: multiple Dose: 200 mg, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/25239610 Page: p.5, 25	unhealthy, ADULT n = 17 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 17 Sources: https://pubmed.ncbi.nlm.nih.gov/25239610 Page: p.5, 25
Dermatitis acneiform	grade 3, 5.9% DLT	200 mg 1 times / week multiple, oral MTD Dose: 200 mg, 1 times / week Route: oral Route: multiple Dose: 200 mg, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/25239610 Page: p.5, 25	unhealthy, ADULT n = 17 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 17 Sources: https://pubmed.ncbi.nlm.nih.gov/25239610 Page: p.5, 25
Erythematous rash	grade 3, 5% DLT	60 mg 1 times / 2 days multiple, oral MTD Dose: 60 mg, 1 times / 2 days Route: oral Route: multiple Dose: 60 mg, 1 times / 2 days Sources: https://pubmed.ncbi.nlm.nih.gov/22025163 Page: p.4690	unhealthy, ADULT n = 20 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 20 Sources: https://pubmed.ncbi.nlm.nih.gov/22025163 Page: p.4690
Skin rash	grade 3, 18.4% DLT, Disc. AE	60 mg 1 times / 2 days multiple, oral MTD Dose: 60 mg, 1 times / 2 days Route: oral Route: multiple Dose: 60 mg, 1 times / 2 days Sources: https://pubmed.ncbi.nlm.nih.gov/25239610 Page: sup. table1	unhealthy, ADULT n = 38 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 38 Sources: https://pubmed.ncbi.nlm.nih.gov/25239610 Page: sup. table1
Stomatitis	grade 3, 2.6% DLT	60 mg 1 times / 2 days multiple, oral MTD Dose: 60 mg, 1 times / 2 days Route: oral Route: multiple Dose: 60 mg, 1 times / 2 days Sources: https://pubmed.ncbi.nlm.nih.gov/25239610 Page: sup. table1	unhealthy, ADULT n = 38 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 38 Sources: https://pubmed.ncbi.nlm.nih.gov/25239610 Page: sup. table1
Skin rash	grade 3, 2.6% DLT, Disc. AE	60 mg 1 times / 2 days multiple, oral MTD Dose: 60 mg, 1 times / 2 days Route: oral Route: multiple Dose: 60 mg, 1 times / 2 days Sources: https://pubmed.ncbi.nlm.nih.gov/25239610 Page: sup. table1	unhealthy, ADULT n = 38 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 38 Sources: https://pubmed.ncbi.nlm.nih.gov/25239610 Page: sup. table1
Skin rash	grade 3, 5.3% DLT	60 mg 1 times / 2 days multiple, oral MTD Dose: 60 mg, 1 times / 2 days Route: oral Route: multiple Dose: 60 mg, 1 times / 2 days Sources: https://pubmed.ncbi.nlm.nih.gov/25239610 Page: sup. table1	unhealthy, ADULT n = 38 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 38 Sources: https://pubmed.ncbi.nlm.nih.gov/25239610 Page: sup. table1
Stomatitis	grade 3, 14.3% DLT	90 mg 1 times / 2 days multiple, oral Studied dose Dose: 90 mg, 1 times / 2 days Route: oral Route: multiple Dose: 90 mg, 1 times / 2 days Sources: https://pubmed.ncbi.nlm.nih.gov/22025163 Page: p.4690	unhealthy, ADULT n = 7 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 7 Sources: https://pubmed.ncbi.nlm.nih.gov/22025163 Page: p.4690
Erythematous rash	grade 3-4, 57.1% DLT	90 mg 1 times / 2 days multiple, oral Studied dose Dose: 90 mg, 1 times / 2 days Route: oral Route: multiple Dose: 90 mg, 1 times / 2 days Sources: https://pubmed.ncbi.nlm.nih.gov/22025163 Page: p.4690	unhealthy, ADULT n = 7 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 7 Sources: https://pubmed.ncbi.nlm.nih.gov/22025163 Page: p.4690

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587	inhibitor 1767	inhibitor 1852

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
MRP1 106 CYP19A1 60 P-gp 1461 BCRP 699	CYP3A 191	CYP3A 129

Drug as perpetrator

Target	Modality	Activity
P-gp 1650	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/31401398/	moder
CYP2C9 1819	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/24387695/	moderate [IC50 >35 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/24387695/ \| https://pubchem.ncbi.nlm.nih.gov/bioassay/1645840#sid=170466896	moderate [IC50 >35 uM]
CYP3A4 1925	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/24387695/	moderate [IC50 >35 uM]
MRP1 172	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/31401398/	moderate [Inhibition 10 uM]
BCRP 773	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/31401398/	moderate
CYP19A1 60	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/743083#sid=144206919	no
CYP3A 298	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/24387695/	yes

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
CYP3A 191	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/24387695/	major

PubMed

Title	Date	PubMed
The Akt-specific inhibitor MK2206 selectively inhibits thyroid cancer cells harboring mutations that can activate the PI3K/Akt pathway.	2011 Apr	21289267
Harnessing the PI3K/Akt/mTOR pathway in T-cell acute lymphoblastic leukemia: eliminating activity by targeting at different levels.	2012 Aug	22885370
PI3K signaling mediates diverse regulation of ATF4 expression for the survival of HK-2 cells exposed to cadmium.	2014 Feb	24057571
Effects of AKT inhibition on HGF-mediated erlotinib resistance in non-small cell lung cancer cell lines.	2015 Apr	25323938
The Akt inhibitor MK-2206 enhances the cytotoxicity of paclitaxel (Taxol) and cisplatin in ovarian cancer cells.	2015 Jan	25164962

Patents

Sample Use Guides

In Vivo Use Guide

90 mg weekly (1st 28 days cycle); 135 mg weekly (2nd 28 days cycle)

Route of Administration: Oral

In Vitro Use Guide

MK-2206 alone more potently inhibited the cell growth of Ras wild-type (WT) cell lines (A431, HCC827, and NCI-H292; IC50s of 5.5, 4.3, and 5.2 μmol/L, respectively) as compared with Ras-mutant cell lines (NCI-H358, NCI-H23, NCI-H1299, and Calu-6; IC50s of 13.5, 14.1, 27.0, and 28.6 μmol/L, respectively), with the exception of NCI-H460, which has a PIK3CA E545K mutation (IC50, 3.4 μmol/L).

Substance Class	Chemical Created by `admin` on `Fri Dec 15 19:50:57 GMT 2023` Edited by `admin` on `Fri Dec 15 19:50:57 GMT 2023`
Record UNII	4HA45S22ZZ
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

MK-2206

Common Name

English

MK-2206 [WHO-DD]

Common Name

English

8-(4-(1-AMINOCYCLOBUTYL)PHENYL)-9-PHENYL-1,2,4-TRIAZOLO(3,4-F)(1,6)NAPHTHYRIDIN-3(2H)-ONE HYDROCHLORIDE (1:1)

Systematic Name

English

MK2206

Code

English

Classification Tree Code System Code

FDA ORPHAN DRUG

291309