LY3009120
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MedKoo CAT#: 206161

CAS#: 1454682-72-4

Description: LY3009120, also known as DP-4978, is potent and selective pan-RAF inhibitor with potential anticancer activity. LY3009120 showed activities against BRaf or Ras mutant tumor cells . LY3009120 binds to ARaf, BRaf and CRaf isoforms with similar affinity in cells with activating mutations of BRaf or KRas. LY3009120 induces minimal paradoxical pathway activation in NRas or KRas mutant cells. LY3009120 inhibits MEK phosphorylation and cell proliferation in vitro, and exhibits anti-tumor activity in multiple xenograft models carrying mutations in BRaf, NRas or KRas.


Chemical Structure

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LY3009120
CAS# 1454682-72-4

Theoretical Analysis

MedKoo Cat#: 206161
Name: LY3009120
CAS#: 1454682-72-4
Chemical Formula: C23H29FN6O
Exact Mass: 424.23869
Molecular Weight: 424.52
Elemental Analysis: C, 65.07; H, 6.89; F, 4.48; N, 19.80; O, 3.77

Price and Availability

Size Price Availability Quantity
10.0mg USD 150.0 Same day
25.0mg USD 250.0 Same day
50.0mg USD 450.0 Same day
100.0mg USD 750.0 Same day
200.0mg USD 1250.0 Same day
500.0mg USD 2250.0 Same day
1.0g USD 3450.0 Same day
2.0g USD 5850.0 2 Weeks
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Synonym: LY3009120; LY-3009120; LY 3009120; DP4978; DP 4978; DP-4978.

IUPAC/Chemical Name: 1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea

InChi Key: HHCBMISMPSAZBF-UHFFFAOYSA-N

InChi Code: 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)

SMILES Code: O=C(NC1=CC(C2=CC3=CN=C(NC)N=C3N=C2C)=C(C)C=C1F)NCCC(C)(C)C

Appearance: Light yellow solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: LY03009120 (DP-4978) is a potent pan-Raf inhibitor with IC50 of 44 nM, 31-47 nM, and 42 nM for A-raf, B-Raf, and C-Raf in A375 cells, respectively.
In vitro activity: The effects of LY3009120 on a panel of CRC cell lines based on BRAFmut and KRASmut background were assessed. Biochemical assay data demonstrated inhibition of BRAFV600E, BRAFWT and CRAFWT with IC50 values of 5.8, 9.1 and 15 nM respectively. In the whole-cell based KiNativ assay measuring the affinity of LY3009120 to each RAF isoform, the IC50 was similar among the three RAF isoforms, specifically, 44, 31-47 and 42 nM for ARAF, BRAF and CRAF respectively. Based on the biochemical and KiNativ assay results, the anti-proliferative effects of LY3009120 using concentrations of low nM up to 10 μM were examined. The anti-proliferative effects of LY3009120 assayed by CellTiter Glo (CTG) and EC50 values were plotted according to the mutational status of each cell line. Cell lines harboring BRAFV600E mutations were the most sensitive to LY3009120, followed by cell lines harboring KRASG13 and KRASG12 mutations (Figure 1A). There was a >5-fold difference between the most sensitive lines (BRAFmut and KRASmut) and the least sensitive lines (KRASWT/BRAFWT) (Figure 1A). Of note, sensitivity of CRC cell lines to LY3009120 could not be predicted based on the activation status of the MAPK and PI3K signaling cascades, but rather appeared to be a function of the BRAF and KRAS mutational status (Figure 1A and 1C). For example, the cell line SW480 (KRASmut) was slightly less responsive to LY3009120 than LoVo (KRASmut) despite SW480 exhibiting lower levels of pERK1/2 (Figure 1C). Reference: Oncotarget. 2017 Feb 7;8(6):9251-9266. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/27999210/
In vivo activity: The in vivo efficacy of LY3009120 was evaluated in CRC xenograft models of various mutational backgrounds. Treatment of Colo 205 xenografts (BRAFmut) with LY3009120 resulted in statistically significant tumor regression (46.7% regression from baseline, p < 0.001) (Figure 5A, top left panel), while treatment of HCT 116 xenografts (KRASmut) resulted in statistically significant inhibition of tumor growth (delta(T/C)= 35.4%, p < 0.01) (Figure 5A, top right panel). Examination of an additional BRAFmut xenograft model, HT-29, confirmed the in vivo efficacy of LY3009120 (delta(T/C)= 40%, p < 0.001) in a BRAFmut CRC setting (Figure 5A, lower left panel), while LY3009120-treatment of Colo 320HSR (KRASWT/BRAFWT) indicated lack of in vivo efficacy in a KRASWT/BRAFWT xenograft model (Figure5A, lower right panel). Reference: Oncotarget. 2017 Feb 7;8(6):9251-9266. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/27999210/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 20.0 47.11

Preparing Stock Solutions

The following data is based on the product molecular weight 424.52 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
In vitro protocol: 1. Vakana E, Pratt S, Blosser W, Dowless M, Simpson N, Yuan XJ, Jaken S, Manro J, Stephens J, Zhang Y, Huber L, Peng SB, Stancato LF. LY3009120, a panRAF inhibitor, has significant anti-tumor activity in BRAF and KRAS mutant preclinical models of colorectal cancer. Oncotarget. 2017 Feb 7;8(6):9251-9266. doi: 10.18632/oncotarget.14002. PMID: 27999210; PMCID: PMC5354729. 2. Yang SM, Park YK, Kim JI, Lee YH, Lee TY, Jang BC. LY3009120, a pan-Raf kinase inhibitor, inhibits adipogenesis of 3T3-L1 cells by controlling the expression and phosphorylation of C/EBP-α, PPAR-γ, STAT‑3, FAS, ACC, perilipin A, and AMPK. Int J Mol Med. 2018 Dec;42(6):3477-3484. doi: 10.3892/ijmm.2018.3890. Epub 2018 Sep 21. PMID: 30272260.
In vivo protocol: 1. Vakana E, Pratt S, Blosser W, Dowless M, Simpson N, Yuan XJ, Jaken S, Manro J, Stephens J, Zhang Y, Huber L, Peng SB, Stancato LF. LY3009120, a panRAF inhibitor, has significant anti-tumor activity in BRAF and KRAS mutant preclinical models of colorectal cancer. Oncotarget. 2017 Feb 7;8(6):9251-9266. doi: 10.18632/oncotarget.14002. PMID: 27999210; PMCID: PMC5354729.

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Additional Information

  LY3009120 is a potentially best-in-class inhibitor of three Raf isoforms and Raf dimer, with activity against tumor cells with BRaf, NRas or KRas mutations, as well as melanoma cells with acquired resistance to current BRaf therapies.