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

Structure Search

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

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/20028854 | https://www.ncbi.nlm.nih.gov/pubmed/22143671https://www.ncbi.nlm.nih.gov/pubmed/22843211
Curator's Comment: description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/23375793 | https://www.ncbi.nlm.nih.gov/pubmed/20561789 | https://www.ncbi.nlm.nih.gov/pubmed/20364113 | https://clinicaltrials.gov/ct2/show/NCT01316809

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 Target ID: CHEMBL2842 Sources: https://www.ncbi.nlm.nih.gov/pubmed/20028854	Inhibitor 8297	0.8 nM [IC50]
Mammalian target of Rapamycin (mTORC1) 23 Target ID: CHEMBL2221341 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23375793	Inhibitor 8297	27.0 nM [IC50]
Serine/threonine-protein kinase mTOR 35 Target ID: CHEMBL2842 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23375793	Inhibitor 8297	0.13 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Solid tumors 145 Sources: https://clinicaltrials.gov/ct2/show/NCT00731263 http://adisinsight.springer.com/drugs/800028731	Primary	Phase I 428	Unknown Approved Use Unknown
Solid tumors 145 Sources: https://clinicaltrials.gov/ct2/show/NCT00973076	Primary	Phase I 428	Unknown Approved Use Unknown
Malignant glioma 10 Sources: https://clinicaltrials.gov/ct2/show/NCT01316809	Primary	Phase I 428	Unknown Approved Use Unknown
Oligodendroglioma 2 Sources: https://clinicaltrials.gov/ct2/show/NCT01316809	Primary	Phase I 428	Unknown Approved Use Unknown
Anaplastic astrocytoma 6 Sources: https://clinicaltrials.gov/ct2/show/NCT01316809	Primary	Phase I 428	Unknown Approved Use Unknown
Glioblastoma multiforme 30 Sources: https://clinicaltrials.gov/ct2/show/NCT01316809	Primary	Phase I 428	Unknown Approved Use Unknown
Hepatocellular carcinoma 83 Sources: https://clinicaltrials.gov/ct2/show/NCT00999882	Primary	Phase I 428	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
70 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22935583	90 mg single, oral dose: 90 mg route of administration: Oral experiment type: SINGLE co-administered:	AZD-8055 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
355 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22935583	120 mg 2 times / day steady-state, oral dose: 120 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	AZD-8055 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
70.1 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22935583	90 mg single, oral dose: 90 mg route of administration: Oral experiment type: SINGLE co-administered:	AZD-8055 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
177 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22935583	120 mg single, oral dose: 120 mg route of administration: Oral experiment type: SINGLE co-administered:	AZD-8055 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

AUC

Value	Dose	Analyte	Population
122 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22935583	90 mg single, oral dose: 90 mg route of administration: Oral experiment type: SINGLE co-administered:	AZD-8055 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
501 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22935583	120 mg 2 times / day steady-state, oral dose: 120 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	AZD-8055 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
134 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22935583	90 mg single, oral dose: 90 mg route of administration: Oral experiment type: SINGLE co-administered:	AZD-8055 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
294 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22935583	120 mg single, oral dose: 120 mg route of administration: Oral experiment type: SINGLE co-administered:	AZD-8055 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

T_1/2

Value	Dose	Analyte	Population
2.63 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22935583	90 mg single, oral dose: 90 mg route of administration: Oral experiment type: SINGLE co-administered:	AZD-8055 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
2.45 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22935583	120 mg 2 times / day steady-state, oral dose: 120 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	AZD-8055 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
2.36 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22935583	90 mg single, oral dose: 90 mg route of administration: Oral experiment type: SINGLE co-administered:	AZD-8055 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
3.14 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22935583	120 mg single, oral dose: 120 mg route of administration: Oral experiment type: SINGLE co-administered:	AZD-8055 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
			inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1461	Human hepatocytes 2 P-gp 1537 BCRP 561

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
P-gp 1650	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/29720580/	yes

Drug as victim

Target	Modality	Activity
BCRP 561	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/27553832/	yes
Human hepatocytes 2	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/23375793/	yes
P-gp 1537	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/27553832/	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://pubmed.ncbi.nlm.nih.gov/23375793/

PubMed

Title	Date	PubMed
		252160253
Regulation of longevity and stress resistance by Sch9 in yeast.	2001 Apr 13	11292860
Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton.	2004 Jul 27	15268862
Simultaneous inhibition of mTORC1 and mTORC2 by mTOR kinase inhibitor AZD8055 induces autophagy and cell death in cancer cells.	2010 May	20364113
Effect of PI3K- and mTOR-specific inhibitors on spontaneous B-cell follicular lymphomas in PTEN/LKB1-deficient mice.	2011 Mar 29	21407213
PI3Kδ inhibition augments the efficacy of rapamycin in suppressing proliferation of Epstein-Barr virus (EBV)+ B cell lymphomas.	2013 Aug	23841834
mTOR/p70S6K signaling distinguishes routine, maintenance-level autophagy from autophagic cell death during influenza A infection.	2014 Mar	24606695

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.

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

Code System Code Type Description

PUBCHEM

25262965