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
MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo.	2010 Jul	20571069
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
Phosphatidylinositol 3-kinase/Akt signaling pathway activates the WNK-OSR1/SPAK-NCC phosphorylation cascade in hyperinsulinemic db/db mice.	2012 Oct	22949526
Detection of key enzymes, free radical reaction products and activated signaling molecules as biomarkers of cell damage induced by benzo[a]pyrene in human keratinocytes.	2014 Aug	24685774
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
Taurocholate Induces Cyclooxygenase-2 Expression via the Sphingosine 1-phosphate Receptor 2 in a Human Cholangiocarcinoma Cell Line.	2015 Dec 25	26518876
The Akt inhibitor MK-2206 enhances the cytotoxicity of paclitaxel (Taxol) and cisplatin in ovarian cancer cells.	2015 Jan	25164962
Elucidating mechanisms of toxicity using phenotypic data from primary human cell systems--a chemical biology approach for thrombosis-related side effects.	2015 Jan 5	25569083
Utilization of human nuclear receptors as an early counter screen for off-target activity: a case study with a compendium of 615 known drugs.	2015 Jun	25752796
S6 inhibition contributes to isoflurane neurotoxicity in the developing brain.	2015 Mar 4	25597859

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