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=C(CO)C=C(C=C1)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

Description

AstraZeneca was developing AZD-8055, an orally active mTORC1/mTORC2 inhibitor, for the treatment of advanced solid tumours. AZD-8055 is an ATP-competitive mTORC1/2 inhibitor that exhibits immunosuppressive and anticancer chemotherapeutic activities. AZD-8055 promotes antibody class switching in B cells at low doses and decreases B cell proliferation and differentiation at high doses. In vivo, this compound suppresses CC4 and CD8 T cell proliferation, increasing survival among MHC-mismatched heart transplant recipients. In vitro, AZD-8055 decreases viability of brain tumor cells; in vivo, it inhibits tumor growth. AZD-8055 had been in phase I trials by AstraZeneca for the treatment of malignant gliomas and solid tumours. However, this research has been discontinued.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Serine/threonine-protein kinase mTOR 35	Inhibitor 8,504		0.8 nM [IC50]
Mammalian target of Rapamycin (mTORC1) 23	Inhibitor 8,504		27.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Solid tumors 147	Primary	Phase I 438	Unknown
Malignant glioma 10	Primary	Phase I 438	Unknown
Oligodendroglioma 2	Primary	Phase I 438	Unknown
Anaplastic astrocytoma 6	Primary	Phase I 438	Unknown
Glioblastoma multiforme 30	Primary	Phase I 438	Unknown
Hepatocellular carcinoma 83	Primary	Phase I 438	Unknown

C_max

Value	Dose	Analyte	Population
177 ng/mL	120 mg single, oral	AZD-8055 plasma	Homo sapiens
70.1 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 ng/mL	90 mg single, oral	AZD-8055 plasma	Homo sapiens

AUC

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

T_1/2

Value	Dose	Analyte	Population
3.14 h	120 mg single, oral	AZD-8055 plasma	Homo sapiens
2.36 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
2.63 h	90 mg single, oral	AZD-8055 plasma	Homo sapiens

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
			inhibitor 2,217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1,741	Human hepatocytes 3 P-gp 2,052 BCRP 697

Drug as perpetrator

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Target	Modality	Activity	Metabolite	Clinical evidence
P-gp 1,932	inhibitor 4,027	yes

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Drug as victim

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Target	Modality	Activity
BCRP 697	substrate 4,014	yes
Human hepatocytes 3	substrate 4,014	yes
P-gp 2,052	substrate 4,014	yes

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2,263	inhibitor 2,237

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PubMed

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Title	Date	PubMed
AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity.	2010 Jan 1	20028854
TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO.	2012 May 2	22560223
Optimization of potent and selective dual mTORC1 and mTORC2 inhibitors: the discovery of AZD8055 and AZD2014.	2013 Mar 1	23375793

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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.

Show entries

Name

Type

Language

AZD-8055

Code

English

AZ-12600000

Preferred Name

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

Showing 1 to 5 of 9 entries

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ACTIVE MOIETY


					970JJ37FPW

AZD-8055

SALT/SOLVATE (PARENT)


					R339J08R6U

AZD-8055 FUMARATE

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