AZD-8055

Investigational

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C25H31N5O4
Molecular Weight	465.5447
Optical Activity	UNSPECIFIED
Defined Stereocenters	2 / 2
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

COC1=CC=C(C=C1CO)C2=NC3=NC(=NC(N4CCOC[C@@H]4C)=C3C=C2)N5CCOC[C@@H]5C

InChI

InChIKey=KVLFRAWTRWDEDF-IRXDYDNUSA-N

InChI=1S/C25H31N5O4/c1-16-14-33-10-8-29(16)24-20-5-6-21(18-4-7-22(32-3)19(12-18)13-31)26-23(20)27-25(28-24)30-9-11-34-15-17(30)2/h4-7,12,16-17,31H,8-11,13-15H2,1-3H3/t16-,17-/m0/s1

HIDE SMILES / InChI

Molecular Formula	C25H31N5O4
Molecular Weight	465.5447
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

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

Description

AZD8055 is a new ATP-competitive mTOR kinase inhibitor that was developed to overcome the limitations of the first generation of allosteric mTORC1 inhibitors (rapamycin and its analogs) as anticancer agents. AZD8055 potently and selectively inhibits mTOR by directly targeting its catalytic site, which results in the blockade of the activity of both mTORC1 and mTORC2 complexes. It displays antitumoral activity by inhibiting proliferation and/or inducing cell death in various cancer cell models, including ovarian clear cell carcinoma.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Serine/threonine-protein kinase mTOR 35	Inhibitor 8,297	0.8 nM [IC50]
Mammalian target of Rapamycin (mTORC1) 23	Inhibitor 8,297	27.0 nM [IC50]
Serine/threonine-protein kinase mTOR 35	Inhibitor 8,297	0.13 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Solid tumors 145	Primary	Phase I 428	Unknown
Solid tumors 145	Primary	Phase I 428	Unknown
Malignant glioma 10	Primary	Phase I 428	Unknown
Oligodendroglioma 2	Primary	Phase I 428	Unknown
Anaplastic astrocytoma 6	Primary	Phase I 428	Unknown
Glioblastoma multiforme 30	Primary	Phase I 428	Unknown
Hepatocellular carcinoma 83	Primary	Phase I 428	Unknown

C_max

Value	Dose	Analyte	Population
70 ng/mL	90 mg single, oral	AZD-8055 plasma	Homo sapiens
355 ng/mL	120 mg 2 times / day steady-state, oral	AZD-8055 plasma	Homo sapiens
70.1 ng/mL	90 mg single, oral	AZD-8055 plasma	Homo sapiens
177 ng/mL	120 mg single, oral	AZD-8055 plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
122 ng × h/mL	90 mg single, oral	AZD-8055 plasma	Homo sapiens
501 ng × h/mL	120 mg 2 times / day steady-state, oral	AZD-8055 plasma	Homo sapiens
134 ng × h/mL	90 mg single, oral	AZD-8055 plasma	Homo sapiens
294 ng × h/mL	120 mg single, oral	AZD-8055 plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
2.63 h	90 mg single, oral	AZD-8055 plasma	Homo sapiens
2.45 h	120 mg 2 times / day steady-state, oral	AZD-8055 plasma	Homo sapiens
2.36 h	90 mg single, oral	AZD-8055 plasma	Homo sapiens
3.14 h	120 mg single, oral	AZD-8055 plasma	Homo sapiens

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
			inhibitor 1,612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1,461	Human hepatocytes 2 P-gp 1,537 BCRP 561

Drug as perpetrator

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Target	Modality	Activity	Metabolite	Clinical evidence
P-gp 1,650	inhibitor 3,277	yes

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Drug as victim

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Target	Modality	Activity
BCRP 561	substrate 3,367	yes
Human hepatocytes 2	substrate 3,367	yes
P-gp 1,537	substrate 3,367	yes

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1,647	inhibitor 1,626

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PubMed

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Title	Date	PubMed
Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton.	2004 Jul 27	15268862
Effect of PI3K- and mTOR-specific inhibitors on spontaneous B-cell follicular lymphomas in PTEN/LKB1-deficient mice.	2011 Mar 29	21407213

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Patents

Sample Use Guides

In Vivo Use Guide

Mice: administration of AZD-8055 (5mg/kg, Bid) and SAHA (100 mg/kg/d) results in complete tumor growth inhibition in PTEN+/−LKB1+/hypo xenografts without side effects on mice by inhibition of mTORC1 and mTORC2 signaling

Route of Administration: Oral

In Vitro Use Guide

AZD-8055 potently inhibits proliferation in U87MG, A549 and H838 cells with IC50 of 53, 50 and 20 nM, respectively.

Substance Class	Chemical
Record UNII	970JJ37FPW
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

AZD-8055

Code

English

AZ-12600000

Code

English

(5-(2,4-BIS((3S)-3-METHYLMORPHOLIN-4-YL)PYRIDO(2,3-D)PYRIMIDIN-7-YL)-2-METHOXYPHENYL)METHANOL

Systematic Name

English

AZD 8055 [WHO-DD]

Common Name

English

AZD8055

Code

English

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Code System

Code

Type

Description

PUBCHEM

25262965

PRIMARY

FDA UNII

970JJ37FPW

PRIMARY

CAS

1009298-09-2

PRIMARY

ChEMBL

CHEMBL1801204

PRIMARY

EPA CompTox

DTXSID001020704

PRIMARY

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Related Record

Type

Details


					R339J08R6U

AZD-8055 FUMARATE

SALT/SOLVATE -> PARENT

Amount:


					1788PW098Q

SERINE/THREONINE-PROTEIN KINASE MTOR

TARGET -> INHIBITOR

Comments:

Using the truncated recombinant mTOR enzyme.

Qualification:

IC50

Amount:

0.13 NANOMOLAR [0.08 to 0.18] (average)


					1788PW098Q

SERINE/THREONINE-PROTEIN KINASE MTOR

TARGET -> INHIBITOR

Comments:

Using native mTOR enzyme complexes extracted from HeLa cells

Qualification:

IC50

Amount:

0.8 NANOMOLAR [0.6 to 1] (average)


					1OHI4ZB7S1

MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1

TARGET -> INHIBITOR

Amount:


					MIF1PZF1OC

MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2

TARGET -> INHIBITOR

Amount:

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Related Record

Type

Details


					970JJ37FPW

AZD-8055

ACTIVE MOIETY

Amount:

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SMILES

InChI

CNS Activity

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

PubMed

Patents

Sample Use Guides

C_max

T_1/2

Drug as perpetrator