SITRAVATINIB MALATE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C33H29F2N5O4S.C4H6O5
Molecular Weight	763.764
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

O[C@@H](CC(O)=O)C(O)=O.COCCNCC1=CN=C(C=C1)C2=CC3=NC=CC(OC4=CC=C(NC(=O)C5(CC5)C(=O)NC6=CC=C(F)C=C6)C=C4F)=C3S2

InChI

InChIKey=GDLGZWLGDROYHH-WNQIDUERSA-N

InChI=1S/C33H29F2N5O4S.C4H6O5/c1-43-15-14-36-18-20-2-8-25(38-19-20)29-17-26-30(45-29)28(10-13-37-26)44-27-9-7-23(16-24(27)35)40-32(42)33(11-12-33)31(41)39-22-5-3-21(34)4-6-22;5-2(4(8)9)1-3(6)7/h2-10,13,16-17,19,36H,11-12,14-15,18H2,1H3,(H,39,41)(H,40,42);2,5H,1H2,(H,6,7)(H,8,9)/t;2-/m.0/s1

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/26675259
Curator's Comment: The description was created based on several sources, including https://encrypted.google.com/patents/WO2009026717A1 | https://clinicaltrials.gov/ct2/show/NCT03015740 | https://clinicaltrials.gov/ct2/show/NCT02978859

MG-516 (Sitravatinib) is a receptor tyrosine kinase (RTK) inhibitor shown in preclinical models to inhibit a closely related spectrum of RTKs including MET, AXL, MER, and members of the VEGFR, PDGFR, DDR2, TRK and Eph families. Broad-spectrum inhibition of multiple RTK signaling pathways by MGCD516 both in vitro and in vivo results in superior activity compared to imatinib and crizotinib. Clinical trials with MGCD516 is currently undergoing.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Ephrin type-A receptor 3 2 Target ID: CHEMBL4954 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26675259	Inhibitor 8297	1.0 nM [IC50]
Tyrosine-protein kinase receptor UFO 14 Target ID: CHEMBL4895 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26675259	Inhibitor 8297	1.5 nM [IC50]
Discoidin domain-containing receptor 2 2 Target ID: CHEMBL5122 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26675259	Inhibitor 8297	0.5 nM [IC50]
Proto-oncogene tyrosine-protein kinase MER 4 Target ID: CHEMBL5331 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26675259	Inhibitor 8297	2.0 nM [IC50]
Vascular endothelial growth factor receptor 3 41 Target ID: CHEMBL1955 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26675259	Inhibitor 8297	2.0 nM [IC50]
Mast/stem cell growth factor receptor Kit 5 Target ID: P10721 Gene ID: 3815.0 Gene Symbol: KIT Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/26675259	Inhibitor 8297	6.0 nM [IC50]
Hepatocyte growth factor receptor 54 Target ID: P08581 Gene ID: 4233.0 Gene Symbol: MET Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/26675259	Inhibitor 8297	20.0 nM [IC50]
Ephrin type-A receptor 3 2 Target ID: P29320 Gene ID: 2042.0 Gene Symbol: EPHA3 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/26675259	Inhibitor 8297	1.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Cancer 592 Sources: https://encrypted.google.com/patents/WO2009026717A1	Primary	Phase I 428	Unknown Approved Use Unknown
Renal cell carcinoma 31 Sources: https://clinicaltrials.gov/ct2/show/NCT03015740	Primary	Phase II 1132	Unknown Approved Use Unknown
Liposarcoma 6 Sources: https://clinicaltrials.gov/ct2/show/NCT02978859	Primary	Phase II 1132	Unknown Approved Use Unknown
Non-small cell lung cancer 206 Sources: https://clinicaltrials.gov/ct2/show/NCT02954991	Primary	Phase II 1132	Unknown Approved Use Unknown
Metastatic liposarcoma 2 Sources: https://clinicaltrials.gov/ct2/show/NCT02978859	Primary	Phase II 1132	Unknown Approved Use Unknown
Non-small cell lung cancer 206 Sources: https://clinicaltrials.gov/ct2/show/NCT02954991	Primary	Phase II 1132	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
21 ng/mL OTHER https://www.mirati.com/wp-content/uploads/Mirati-516-003-SITC-2019-Final-Slides-web.pdf	120 mg single, oral dose: 120 mg route of administration: Oral experiment type: SINGLE co-administered:		SITRAVATINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
72.5 ng/mL OTHER https://www.mirati.com/wp-content/uploads/Mirati-516-003-SITC-2019-Final-Slides-web.pdf	120 mg 1 times / day steady-state, oral dose: 120 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		SITRAVATINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
200 mg 1 times / day multiple, oral (unknown) Highest studied dose Dose: 200 mg, 1 times / day Route: oral Route: multiple Dose: 200 mg, 1 times / day Sources: https://www.mirati.com/wp-content/uploads/20160603_A-First-in-Human-Phase-1-Study-of-Receptor-Tyrosine-Kinase-RTK-Inhibitor-MGCD516-in-Patients-with-Advanced-Solid-Tumors.pdf	unhealthy n = 3 Health Status: unhealthy Condition: Advanced Solid Tumors Sex: M+F Food Status: UNKNOWN Population Size: 3 Sources: https://www.mirati.com/wp-content/uploads/20160603_A-First-in-Human-Phase-1-Study-of-Receptor-Tyrosine-Kinase-RTK-Inhibitor-MGCD516-in-Patients-with-Advanced-Solid-Tumors.pdf	DLT: Mucositis, Neuropathy... Dose limiting toxicities: Mucositis (grade 2, 1 pt) Neuropathy (grade 2, 1 pt) Fatigue (grade 2, 1 pt) Sources: https://www.mirati.com/wp-content/uploads/20160603_A-First-in-Human-Phase-1-Study-of-Receptor-Tyrosine-Kinase-RTK-Inhibitor-MGCD516-in-Patients-with-Advanced-Solid-Tumors.pdf
80 mg 1 times / day multiple, oral Studied dose Dose: 80 mg, 1 times / day Route: oral Route: multiple Dose: 80 mg, 1 times / day Sources: https://www.mirati.com/wp-content/uploads/20160603_A-First-in-Human-Phase-1-Study-of-Receptor-Tyrosine-Kinase-RTK-Inhibitor-MGCD516-in-Patients-with-Advanced-Solid-Tumors.pdf	unhealthy n = 6 Health Status: unhealthy Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: https://www.mirati.com/wp-content/uploads/20160603_A-First-in-Human-Phase-1-Study-of-Receptor-Tyrosine-Kinase-RTK-Inhibitor-MGCD516-in-Patients-with-Advanced-Solid-Tumors.pdf	DLT: Palmar-plantar erythrodysesthesia... Dose limiting toxicities: Palmar-plantar erythrodysesthesia (grade 3, 1 pt) Sources: https://www.mirati.com/wp-content/uploads/20160603_A-First-in-Human-Phase-1-Study-of-Receptor-Tyrosine-Kinase-RTK-Inhibitor-MGCD516-in-Patients-with-Advanced-Solid-Tumors.pdf

AEs

AE	Significance	Dose	Population
Fatigue	grade 2, 1 pt DLT	200 mg 1 times / day multiple, oral (unknown) Highest studied dose Dose: 200 mg, 1 times / day Route: oral Route: multiple Dose: 200 mg, 1 times / day Sources: https://www.mirati.com/wp-content/uploads/20160603_A-First-in-Human-Phase-1-Study-of-Receptor-Tyrosine-Kinase-RTK-Inhibitor-MGCD516-in-Patients-with-Advanced-Solid-Tumors.pdf	unhealthy n = 3 Health Status: unhealthy Condition: Advanced Solid Tumors Sex: M+F Food Status: UNKNOWN Population Size: 3 Sources: https://www.mirati.com/wp-content/uploads/20160603_A-First-in-Human-Phase-1-Study-of-Receptor-Tyrosine-Kinase-RTK-Inhibitor-MGCD516-in-Patients-with-Advanced-Solid-Tumors.pdf
Mucositis	grade 2, 1 pt DLT	200 mg 1 times / day multiple, oral (unknown) Highest studied dose Dose: 200 mg, 1 times / day Route: oral Route: multiple Dose: 200 mg, 1 times / day Sources: https://www.mirati.com/wp-content/uploads/20160603_A-First-in-Human-Phase-1-Study-of-Receptor-Tyrosine-Kinase-RTK-Inhibitor-MGCD516-in-Patients-with-Advanced-Solid-Tumors.pdf	unhealthy n = 3 Health Status: unhealthy Condition: Advanced Solid Tumors Sex: M+F Food Status: UNKNOWN Population Size: 3 Sources: https://www.mirati.com/wp-content/uploads/20160603_A-First-in-Human-Phase-1-Study-of-Receptor-Tyrosine-Kinase-RTK-Inhibitor-MGCD516-in-Patients-with-Advanced-Solid-Tumors.pdf
Neuropathy	grade 2, 1 pt DLT	200 mg 1 times / day multiple, oral (unknown) Highest studied dose Dose: 200 mg, 1 times / day Route: oral Route: multiple Dose: 200 mg, 1 times / day Sources: https://www.mirati.com/wp-content/uploads/20160603_A-First-in-Human-Phase-1-Study-of-Receptor-Tyrosine-Kinase-RTK-Inhibitor-MGCD516-in-Patients-with-Advanced-Solid-Tumors.pdf	unhealthy n = 3 Health Status: unhealthy Condition: Advanced Solid Tumors Sex: M+F Food Status: UNKNOWN Population Size: 3 Sources: https://www.mirati.com/wp-content/uploads/20160603_A-First-in-Human-Phase-1-Study-of-Receptor-Tyrosine-Kinase-RTK-Inhibitor-MGCD516-in-Patients-with-Advanced-Solid-Tumors.pdf
Palmar-plantar erythrodysesthesia	grade 3, 1 pt DLT	80 mg 1 times / day multiple, oral Studied dose Dose: 80 mg, 1 times / day Route: oral Route: multiple Dose: 80 mg, 1 times / day Sources: https://www.mirati.com/wp-content/uploads/20160603_A-First-in-Human-Phase-1-Study-of-Receptor-Tyrosine-Kinase-RTK-Inhibitor-MGCD516-in-Patients-with-Advanced-Solid-Tumors.pdf	unhealthy n = 6 Health Status: unhealthy Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: https://www.mirati.com/wp-content/uploads/20160603_A-First-in-Human-Phase-1-Study-of-Receptor-Tyrosine-Kinase-RTK-Inhibitor-MGCD516-in-Patients-with-Advanced-Solid-Tumors.pdf

PubMed

Title	Date	PubMed
Significant blockade of multiple receptor tyrosine kinases by MGCD516 (Sitravatinib), a novel small molecule inhibitor, shows potent anti-tumor activity in preclinical models of sarcoma.	2016 Jan 26	26675259

Patents

Sample Use Guides

In Vivo Use Guide

MGCD516 administered at 150 mg daily, in continuous 21 day cycles

Route of Administration: Oral

In Vitro Use Guide

MGCD516 (sitravatinib) treatment was able to inhibit proliferation of LS141 and DDLS cell lines significantly better than pazopanib especially at 1000 nM concentration (p<0.0005) suggesting better pathway inhibition by MGCD516.

Name

Type

Language

SITRAVATINIB MALATE

Official Name

English

MGCD516 MALATE SALT

Code

English

SITRAVATINIB L-MALATE

Common Name

English

N-(3-FLUORO-4-(2-(5-((2-METHOXYETHYLAMINO) METHYL) PYRIDIN-2-YL) THIENO (3,2-B) PYRIDIN- 7-YLOXY) PHENYL)-N-(4-FLUOROPHENYL) CYCLOPROPANE-1,1-DICARBOXAMIDE , L-MALATE SALT

Systematic Name

English

N-(3-FLUORO-4-((2-(5-(((2-METHOXYETHYL)AMINO)METHYL)PYRIDIN-2-YL)THIENO(3,2-B)PYRIDIN-7-YL)OXY)PHENYL)-N'-(4-FLUOROPHENYL)CYCLOPROPANE-1,1-DICARBOXAMIDE (2S)-2-HYDROXYBUTANEDIOATE (1:1)

Common Name

English

SITRAVATINIB MALATE [USAN]

Common Name

English

BUTANEDIOIC ACID, 2-HYDROXY-, (2S)-, COMPD. WITH N-(3-FLUORO-4-((2-(5-(((2-METHOXYETHYL)AMINO)METHYL)-2-PYRIDINYL)THIENO(3,2-B)PYRIDIN-7-YL)OXY)PHENYL)-N'-(4-FLUOROPHENYL)-1,1-CYCLOPROPANEDICARBOXAMIDE (1:1)

Common Name

English

MGCD-516 MALATE SALT

Code

English

MGCD-516 L-MALATE

Code

English

Code System Code Type Description

CAS

2244864-88-6