LY-3009120

Investigational

Details

Stereochemistry	ACHIRAL
Molecular Formula	C23H29FN6O
Molecular Weight	424.5144
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CNC1=NC2=C(C=N1)C=C(C(C)=N2)C3=C(C)C=C(F)C(NC(=O)NCCC(C)(C)C)=C3

InChI

InChIKey=HHCBMISMPSAZBF-UHFFFAOYSA-N

InChI=1S/C23H29FN6O/c1-13-9-18(24)19(29-22(31)26-8-7-23(3,4)5)11-16(13)17-10-15-12-27-21(25-6)30-20(15)28-14(17)2/h9-12H,7-8H2,1-6H3,(H2,26,29,31)(H,25,27,28,30)

HIDE SMILES / InChI

Molecular Formula	C23H29FN6O
Molecular Weight	424.5144
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/25965804
Curator's Comment: The description was created based on several sources, including https://clinicaltrials.gov/ct2/show/NCT02014116 | https://www.ncbi.nlm.nih.gov/pubmed/27999210 | https://encrypted.google.com/patents/WO2013134243A1

LY-3009120 is an orally available inhibitor of all members of the serine/threonine protein kinase Raf family, including A-Raf, B-Raf, and C-Raf protein kinases, with potential antineoplastic activity. Upon administration, pan-RAF kinase inhibitor LY3009120 inhibits Raf-mediated signal transduction pathways, which may inhibit tumor cell growth. Raf protein kinases play a key role in the RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway, which is often dysregulated in human cancers and plays a key role in tumor cell proliferation and survival. LY3009120 is being investigated in phase I clinical trial.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Serine/threonine-protein kinase B-raf 20 Target ID: CHEMBL5145 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25965804	Inhibitor 8297	15.0 nM [IC50]
Serine/threonine-protein kinase RAF 10 Target ID: CHEMBL1906 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25965804	Inhibitor 8297	4.3 nM [IC50]
Ephrin type-A receptor 2 6 Target ID: CHEMBL2068 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25965804	Inhibitor 8297	20.0 nM [IC50]
Serine/threonine-protein kinase A-Raf 3 Target ID: CHEMBL1169596 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25965804	Inhibitor 8297	44.0 nM [IC50]
Mixed lineage kinase 7 1 Target ID: CHEMBL3886 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25965804	Inhibitor 8297	39.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Melanoma 88 Sources: https://clinicaltrials.gov/ct2/show/NCT02014116	Primary	Phase I 428	Unknown Approved Use Unknown
Non-small cell lung cancer 206 Sources: https://clinicaltrials.gov/ct2/show/NCT02014116	Primary	Phase I 428	Unknown Approved Use Unknown
Colorectal cancer 101 Sources: https://clinicaltrials.gov/ct2/show/NCT02014116	Primary	Phase I 428	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
34.4 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25965804	10 mg/kg single, oral dose: 10 mg/kg route of administration: Oral experiment type: SINGLE co-administered:		LY-3009120 plasma	Rattus norvegicus population: HEALTHY age: ADULT sex: MALE food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
169 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25965804	10 mg/kg single, oral dose: 10 mg/kg route of administration: Oral experiment type: SINGLE co-administered:		LY-3009120 plasma	Rattus norvegicus population: HEALTHY age: ADULT sex: MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
1.4 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25965804	10 mg/kg single, oral dose: 10 mg/kg route of administration: Oral experiment type: SINGLE co-administered:		LY-3009120 plasma	Rattus norvegicus population: HEALTHY age: ADULT sex: MALE food status: FASTED

Doses

Dose	Population	Adverse events
500 mg 2 times / day multiple, oral Highest studied dose Dose: 500 mg, 2 times / day Route: oral Route: multiple Dose: 500 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/31645440 Page: p.462, 463	unhealthy, ADULT n = 2 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 2 Sources: https://pubmed.ncbi.nlm.nih.gov/31645440 Page: p.462, 463	DLT: Myalgia, Pain... Dose limiting toxicities: Myalgia (grade 3, 50%) Pain (grade 3, 50%) Stomatitis (grade 3, 50%) Arthralgia (grade 3, 50%) Sources: https://pubmed.ncbi.nlm.nih.gov/31645440 Page: p.462, 463
300 mg 2 times / day multiple, oral RP2D Dose: 300 mg, 2 times / day Route: oral Route: multiple Dose: 300 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/31645440 Page: p.462, 463	unhealthy, ADULT n = 16 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 16 Sources: https://pubmed.ncbi.nlm.nih.gov/31645440 Page: p.462, 463	DLT: Blurred vision, Dermatitis acneiform... Disc. AE: Myalgia... Dose limiting toxicities: Blurred vision (grade 2, 6.25%) Dermatitis acneiform (grade 2, 6.25%) AEs leading to discontinuation/dose reduction: Myalgia (6.25%) Sources: https://pubmed.ncbi.nlm.nih.gov/31645440 Page: p.462, 463

AEs

AE	Significance	Dose	Population
Arthralgia	grade 3, 50% DLT, Disc. AE	500 mg 2 times / day multiple, oral Highest studied dose Dose: 500 mg, 2 times / day Route: oral Route: multiple Dose: 500 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/31645440 Page: p.462, 463	unhealthy, ADULT n = 2 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 2 Sources: https://pubmed.ncbi.nlm.nih.gov/31645440 Page: p.462, 463
Myalgia	grade 3, 50% DLT, Disc. AE	500 mg 2 times / day multiple, oral Highest studied dose Dose: 500 mg, 2 times / day Route: oral Route: multiple Dose: 500 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/31645440 Page: p.462, 463	unhealthy, ADULT n = 2 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 2 Sources: https://pubmed.ncbi.nlm.nih.gov/31645440 Page: p.462, 463
Pain	grade 3, 50% DLT, Disc. AE	500 mg 2 times / day multiple, oral Highest studied dose Dose: 500 mg, 2 times / day Route: oral Route: multiple Dose: 500 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/31645440 Page: p.462, 463	unhealthy, ADULT n = 2 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 2 Sources: https://pubmed.ncbi.nlm.nih.gov/31645440 Page: p.462, 463
Stomatitis	grade 3, 50% DLT, Disc. AE	500 mg 2 times / day multiple, oral Highest studied dose Dose: 500 mg, 2 times / day Route: oral Route: multiple Dose: 500 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/31645440 Page: p.462, 463	unhealthy, ADULT n = 2 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 2 Sources: https://pubmed.ncbi.nlm.nih.gov/31645440 Page: p.462, 463
Myalgia	6.25% Disc. AE	300 mg 2 times / day multiple, oral RP2D Dose: 300 mg, 2 times / day Route: oral Route: multiple Dose: 300 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/31645440 Page: p.462, 463	unhealthy, ADULT n = 16 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 16 Sources: https://pubmed.ncbi.nlm.nih.gov/31645440 Page: p.462, 463
Blurred vision	grade 2, 6.25% DLT	300 mg 2 times / day multiple, oral RP2D Dose: 300 mg, 2 times / day Route: oral Route: multiple Dose: 300 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/31645440 Page: p.462, 463	unhealthy, ADULT n = 16 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 16 Sources: https://pubmed.ncbi.nlm.nih.gov/31645440 Page: p.462, 463
Dermatitis acneiform	grade 2, 6.25% DLT	300 mg 2 times / day multiple, oral RP2D Dose: 300 mg, 2 times / day Route: oral Route: multiple Dose: 300 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/31645440 Page: p.462, 463	unhealthy, ADULT n = 16 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 16 Sources: https://pubmed.ncbi.nlm.nih.gov/31645440 Page: p.462, 463

Sourcing

Vendor/Aggregator	ID	URL
1PlusChem LLC	1P001DII	https://www.1pchem.com/search?query=1P001DII
AChemBlock	H-8969	http://www.achemblock.com/catalogsearch/result/?q=H-8969
Angene	AGN-PC-0WHAC3	http://www.angenechemical.com/productshow/AGN-PC-0WHAC3.html
ApexBio Technology	A8716	https://www.apexbt.com/catalogsearch/result/?q=A8716
AstaTech	C72761	http://astatechinc.com/CPSResult.php?CRNO=C72761
BLD Pharm	BD303416	http://www.bldpharm.com/search/Search.html?keyword=BD303416
Cayman Chemical	21504	http://www.caymanchem.com/app/template/Product.vm/catalog/21504
Chem Scene	CS-4147	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-4147
ChemShuttle	140522	https://www.chemshuttle.com/catalogsearch/result/?q=140522
Excenen	EX-A1638	http://www.excenen.com/searchresultlist.php?id=EX-A1638
KeyOrganics	AS-74984	http://www.keyorganicsinc.com/bionet/catalogsearch/result?q=AS-74984
MedChem Express	HY-12558	https://www.medchemexpress.com/search.html?q=HY-12558&ft=&fa=&fp=
MolPort	MolPort-039-137-278	https://www.molport.com/shop/molecule-link/MolPort-039-137-278
Molnova	M11963	https://www.molnova.com/en/serch-list.html?keywords=M11963
MuseChem	I001758	https://www.musechem.com/product/I001758.html
Selleck Chemicals	S7842	http://www.selleckchem.com/search.html?searchDTO.searchParam=S7842
ShangHai Biochempartner	BCP23869	http://www.biochempartner.com/search_BCP23869
TargetMol	T6882	https://www.targetmol.com/search?keyword=T6882
eMolecules	53744842	https://orderbb.emolecules.com/search/#?query=53744842
mcule	MCULE-7282033383	https://mcule.com/MCULE-7282033383/

PubMed

Title	Date	PubMed
Inhibition of RAF Isoforms and Active Dimers by LY3009120 Leads to Anti-tumor Activities in RAS or BRAF Mutant Cancers.	2015 Sep 14	26343583

Patents

Sample Use Guides

In Vivo Use Guide

LY3009120 in escalating dose cohorts given orally BID (twice daily) every 12 hours for a 28-day cycle

Route of Administration: Oral

In Vitro Use Guide

A375 cells (catalog no. CRL-1619) were obtained from the American Type Culture Collection (ATCC, Manassas, VA). Cells were grown in DMEM high glucose supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, CA) and 1% penicillin/streptomycin/L-glutamine at 37 °C, 5% CO2, and 95% humidity. Cells were allowed to expand until 70−95% confluency at which point they were subcultured or harvested for assay use. A serial dilution of test compound (LY-3009120) was dispensed into a 384-well black clear bottom plate in triplicate. Six-hundred-twenty-five cells were added per well in 50 μL of complete growth medium in the 384-well plate. Plates were incubated for 67 h at 37 °C, 5% CO2, and 95% humidity. At the end of the incubation period, 10 μL of a 440 μM solution of resazurin (Sigma, St. Louis, MO) in PBS was added to each well of the plate and plates were incubated for an additional 5 h at 37 °C, 5% CO2, and 95% humidity. Plates were read on a Synergy2 reader (Biotek, Winooski, VT) using an excitation of 540 nm and an emission of 600 nm.

Substance Class	Chemical Created by `admin` on `Sat Dec 16 01:02:01 UTC 2023` Edited by `admin` on `Sat Dec 16 01:02:01 UTC 2023`
Record UNII	1GDT36RARO
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

LY-3009120

Common Name

English

DP-4978

Code

English

UREA, N-(3,3-DIMETHYLBUTYL)-N'-(2-FLUORO-4-METHYL-5-(7-METHYL-2-(METHYLAMINO)PYRIDO(2,3-D)PYRIMIDIN-6-YL)PHENYL)-

Systematic Name

English

LY3009120

Code

English

PAN-RAF INHIBITOR LY3009120

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C2336