RO-5045337

Investigational

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C38H48Cl2N4O4S
Molecular Weight	727.783
Optical Activity	UNSPECIFIED
Defined Stereocenters	2 / 2
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CCOC1=C(C=CC(=C1)C(C)(C)C)C2=N[C@@](C)(C3=CC=C(Cl)C=C3)[C@](C)(N2C(=O)N4CCN(CCCS(C)(=O)=O)CC4)C5=CC=C(Cl)C=C5

InChI

InChIKey=QBGKPEROWUKSBK-QPPIDDCLSA-N

InChI=1S/C38H48Cl2N4O4S/c1-8-48-33-26-29(36(2,3)4)14-19-32(33)34-41-37(5,27-10-15-30(39)16-11-27)38(6,28-12-17-31(40)18-13-28)44(34)35(45)43-23-21-42(22-24-43)20-9-25-49(7,46)47/h10-19,26H,8-9,20-25H2,1-7H3/t37-,38+/m0/s1

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/24900694
Curator's Comment: description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/26210682 | https://clinicaltrials.gov/ct2/show/NCT01605526 | https://www.ncbi.nlm.nih.gov/pubmed/26459177

RO-5045337 (RG7112) is a small molecule that binds to a MDM2, a negative regulator of tumor-supressor protein p53. It was discovered by Roche and investigated in clinical trials against solid tumors, leukemias and sarcomas.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
p53-binding protein Mdm-2 9 Target ID: CHEMBL5023 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24900694	Inhibitor 8504		18.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Acute myeloid leukemia 141 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26459177	Primary	Phase I 438	Unknown Approved Use Unknown
Chronic myeloid leukemia 24 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26459177	Primary	Phase I 438	Unknown Approved Use Unknown
Acute lymphoblastic leukemia 27 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26459177	Primary	Phase I 438	Unknown Approved Use Unknown
Chronic lymphocytic leukemia 59 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26459177	Primary	Phase I 438	Unknown Approved Use Unknown
Solid tumors 147 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26210682	Primary	Phase I 438	Unknown Approved Use Unknown
Soft tissue sarcoma 10 Sources: https://clinicaltrials.gov/ct2/show/NCT01605526	Primary	Phase I 438	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
6500 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26459177	1000 mg 2 times / day steady-state, oral dose: 1000 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	RO-5045337 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
4611.7 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26459177	1215 mg/m² 2 times / day steady-state, oral dose: 1215 mg/m² route of administration: Oral experiment type: STEADY-STATE co-administered:	RO-5045337 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
5544.3 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26459177	810 mg/m² 2 times / day steady-state, oral dose: 810 mg/m² route of administration: Oral experiment type: STEADY-STATE co-administered:	RO-5045337 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
2518.7 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26459177	405 mg/m² 2 times / day steady-state, oral dose: 405 mg/m² route of administration: Oral experiment type: STEADY-STATE co-administered:	RO-5045337 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
3393 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26459177	1215 mg/m² 1 times / day steady-state, oral dose: 1215 mg/m² route of administration: Oral experiment type: STEADY-STATE co-administered:	RO-5045337 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
4074 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26459177	810 mg/m² 1 times / day steady-state, oral dose: 810 mg/m² route of administration: Oral experiment type: STEADY-STATE co-administered:	RO-5045337 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
4227.5 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26459177	540 mg/m² 1 times / day steady-state, oral dose: 540 mg/m² route of administration: Oral experiment type: STEADY-STATE co-administered:	RO-5045337 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
3075 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26459177	360 mg/m² 1 times / day steady-state, oral dose: 360 mg/m² route of administration: Oral experiment type: STEADY-STATE co-administered:	RO-5045337 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
1080 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26459177	45 mg/m² 1 times / day steady-state, oral dose: 45 mg/m² route of administration: Oral experiment type: STEADY-STATE co-administered:	RO-5045337 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
442.7 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26459177	30 mg/m² 1 times / day steady-state, oral dose: 30 mg/m² route of administration: Oral experiment type: STEADY-STATE co-administered:	RO-5045337 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
112.3 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26459177	20 mg/m² 1 times / day steady-state, oral dose: 20 mg/m² route of administration: Oral experiment type: STEADY-STATE co-administered:	RO-5045337 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
8943 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26459177	1500 mg 2 times / day steady-state, oral dose: 1500 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	RO-5045337 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
5646.7 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26459177	1920 mg/m² 2 times / day steady-state, oral dose: 1920 mg/m² route of administration: Oral experiment type: STEADY-STATE co-administered:	RO-5045337 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
125264.1 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26459177	1000 mg 2 times / day steady-state, oral dose: 1000 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	RO-5045337 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
88065.4 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26459177	1215 mg/m² 2 times / day steady-state, oral dose: 1215 mg/m² route of administration: Oral experiment type: STEADY-STATE co-administered:	RO-5045337 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
100944.3 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26459177	810 mg/m² 2 times / day steady-state, oral dose: 810 mg/m² route of administration: Oral experiment type: STEADY-STATE co-administered:	RO-5045337 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
46137.4 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26459177	405 mg/m² 2 times / day steady-state, oral dose: 405 mg/m² route of administration: Oral experiment type: STEADY-STATE co-administered:	RO-5045337 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
48023.1 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26459177	1215 mg/m² 1 times / day steady-state, oral dose: 1215 mg/m² route of administration: Oral experiment type: STEADY-STATE co-administered:	RO-5045337 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
67189.8 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26459177	810 mg/m² 1 times / day steady-state, oral dose: 810 mg/m² route of administration: Oral experiment type: STEADY-STATE co-administered:	RO-5045337 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
67635.3 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26459177	540 mg/m² 1 times / day steady-state, oral dose: 540 mg/m² route of administration: Oral experiment type: STEADY-STATE co-administered:	RO-5045337 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
49082.4 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26459177	360 mg/m² 1 times / day steady-state, oral dose: 360 mg/m² route of administration: Oral experiment type: STEADY-STATE co-administered:	RO-5045337 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
18842.6 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26459177	45 mg/m² 1 times / day steady-state, oral dose: 45 mg/m² route of administration: Oral experiment type: STEADY-STATE co-administered:	RO-5045337 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
7859.2 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26459177	30 mg/m² 1 times / day steady-state, oral dose: 30 mg/m² route of administration: Oral experiment type: STEADY-STATE co-administered:	RO-5045337 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
1597.2 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26459177	20 mg/m² 1 times / day steady-state, oral dose: 20 mg/m² route of administration: Oral experiment type: STEADY-STATE co-administered:	RO-5045337 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
175528.9 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26459177	1500 mg 2 times / day steady-state, oral dose: 1500 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	RO-5045337 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
89972.3 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26459177	1920 mg/m² 2 times / day steady-state, oral dose: 1920 mg/m² route of administration: Oral experiment type: STEADY-STATE co-administered:	RO-5045337 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Analyte	Population
38.8 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26459177	1000 mg 2 times / day steady-state, oral dose: 1000 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	RO-5045337 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
31.7 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26459177	1215 mg/m² 2 times / day steady-state, oral dose: 1215 mg/m² route of administration: Oral experiment type: STEADY-STATE co-administered:	RO-5045337 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
36 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26459177	810 mg/m² 2 times / day steady-state, oral dose: 810 mg/m² route of administration: Oral experiment type: STEADY-STATE co-administered:	RO-5045337 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
55 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26459177	405 mg/m² 2 times / day steady-state, oral dose: 405 mg/m² route of administration: Oral experiment type: STEADY-STATE co-administered:	RO-5045337 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
41 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26459177	1215 mg/m² 1 times / day steady-state, oral dose: 1215 mg/m² route of administration: Oral experiment type: STEADY-STATE co-administered:	RO-5045337 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
23.7 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26459177	810 mg/m² 1 times / day steady-state, oral dose: 810 mg/m² route of administration: Oral experiment type: STEADY-STATE co-administered:	RO-5045337 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
36.3 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26459177	540 mg/m² 1 times / day steady-state, oral dose: 540 mg/m² route of administration: Oral experiment type: STEADY-STATE co-administered:	RO-5045337 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
22.7 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26459177	360 mg/m² 1 times / day steady-state, oral dose: 360 mg/m² route of administration: Oral experiment type: STEADY-STATE co-administered:	RO-5045337 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
96.2 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26459177	45 mg/m² 1 times / day steady-state, oral dose: 45 mg/m² route of administration: Oral experiment type: STEADY-STATE co-administered:	RO-5045337 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
61.9 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26459177	30 mg/m² 1 times / day steady-state, oral dose: 30 mg/m² route of administration: Oral experiment type: STEADY-STATE co-administered:	RO-5045337 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
58.4 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26459177	20 mg/m² 1 times / day steady-state, oral dose: 20 mg/m² route of administration: Oral experiment type: STEADY-STATE co-administered:	RO-5045337 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
41.1 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26459177	1500 mg 2 times / day steady-state, oral dose: 1500 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	RO-5045337 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
17.2 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26459177	1920 mg/m² 2 times / day steady-state, oral dose: 1920 mg/m² route of administration: Oral experiment type: STEADY-STATE co-administered:	RO-5045337 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
1920 mg/m2 2 times / day multiple, oral Highest studied dose Dose: 1920 mg/m2, 2 times / day Route: oral Route: multiple Dose: 1920 mg/m2, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/26459177	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/26459177	Sources: https://pubmed.ncbi.nlm.nih.gov/26459177
1500 mg 2 times / day multiple, oral MTD Dose: 1500 mg, 2 times / day Route: oral Route: multiple Dose: 1500 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/26459177	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/26459177	Sources: https://pubmed.ncbi.nlm.nih.gov/26459177

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1946 inhibitor 2252

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
CYP3A4 2633	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/26459177/	yes

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
CYP3A4 1946	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/26459177/	yes

PubMed

Title	Date	PubMed
Results of the Phase I Trial of RG7112, a Small-Molecule MDM2 Antagonist in Leukemia.	2016-02-15	26459177
Clinical pharmacology characterization of RG7112, an MDM2 antagonist, in patients with advanced solid tumors.	2015-09	26210682
Discovery of RG7112: A Small-Molecule MDM2 Inhibitor in Clinical Development.	2013-05-09	24900694

Patents

Sample Use Guides

In Vivo Use Guide

In leukemia study the starting dose was 20 mg/m2 of the crystalline formulation of RO-5045337, administered orally once-daily (QD). RO-5045337 was dosed orally for 10 days followed by 18 days of rest in a 28-day cycle.

Route of Administration: Oral

In Vitro Use Guide

To assess the potency of RO-5045337 as inhibitor of the p53-MDM2 interaction, a homogeneous time-resolved fluorescence (HTRF) assay that utilizes the N-terminal domain of recombinant human MDM2 protein and a peptide derived from the binding site of p53 was used. RO-5045337 inhibited binding of a model peptide with MDM2 with IC50 of 18 nM.

Name

Type

Language

RG-7112

Preferred Name

English

RO-5045337

Code

English

R 7112

Code

English

METHANONE, ((4S,5R)-4,5-BIS(4-CHLOROPHENYL)-2-(4-(1,1-DIMETHYLETHYL)-2-ETHOXYPHENYL)-4,5-DIHYDRO-4,5-DIMETHYL-1H-IMIDAZOL-1-YL)(4-(3-(METHYLSULFONYL)PROPYL)-1-PIPERAZINYL)-

Common Name

English

RO5045337

Code

English

R 7112 [WHO-DD]

Common Name

English

RG7112

Code

English

MDM2 ANTAGONIST RO5045337

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C129839