LY345899 | MTHFD1 and MTHFD2 inhibitor | CAS#10538-99-5

MedKoo Cat#: 408012 | Name: LY345899

Description:

WARNING: This product is for research use only, not for human or veterinary use.

LY345899 is a potent, cytoplasmic and mitochondrial methylenetetrahydrofolate dehydrogenase MTHFD1 and MTHFD2 inhibitor. LY345899 inhibited MTHFD2 (IC50: 663 nM) as well as MTHFD1 (IC50: 96 nM),

Chemical Structure

LY345899

CAS#10538-99-5

Theoretical Analysis

MedKoo Cat#: 408012

Name: LY345899

CAS#: 10538-99-5

Chemical Formula: C20H21N7O7

Exact Mass: 471.1502

Molecular Weight: 471.43

Elemental Analysis: C, 50.96; H, 4.49; N, 20.80; O, 23.76

Price and Availability

Size	Price	Availability
5mg	USD 110.00	Ready to ship
10mg	USD 190.00	Ready to ship
25mg	USD 350.00	Ready to ship
50mg	USD 650.00	Ready to ship
100mg	USD 1,150.00	Ready to ship
200mg	USD 1,950.00	Ready to ship

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Related CAS #

No Data

Synonym

LY345899; LY-345899; LY 345899;

IUPAC/Chemical Name

(4-(3-amino-1-hydroxy-9-oxo-5,6,6a,7-tetrahydroimidazo[1,5-f]pteridin-8(9H)-yl)benzoyl)-L-glutamic acid

InChi Key

JSNFRYBHBVDHSG-KIYNQFGBSA-N

InChi Code

InChI=1S/C20H21N7O7/c21-19-24-15-14(17(31)25-19)27-11(7-22-15)8-26(20(27)34)10-3-1-9(2-4-10)16(30)23-12(18(32)33)5-6-13(28)29/h1-4,11-12H,5-8H2,(H,23,30)(H,28,29)(H,32,33)(H4,21,22,24,25,31)/t11?,12-/m0/s1

SMILES Code

O=C(O)CC[C@@H](C(O)=O)NC(C1=CC=C(N2C(N3C4=C(O)N=C(N)N=C4NCC3C2)=O)C=C1)=O

Appearance

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

Shelf Life

>3 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

More Info

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot# A20T12K23

QC Data

View QC data: current batch, Lot#A20T12K23

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

LY 345899 is a Folate analog, a methylene tetrahydrofolate dehydrogenase (MTHFD1; DC301), and MTHFD2 inbhibitor with IC50 values of 96 nM and 663 nM, respectively and a Ki of 18 nM for MTHFD1.

In vitro activity:

LY345899 was synthesized and tested for its antitumor activity in CRC (Figure 7A). The results indicated that LY345899 treatment for 72 hours caused a decrease in the cell viability of the CRC cells with highly expressed MTHFD2 (LoVo, SW620, HCT116) (Figure 7B). These CRC cells treated with low-dose LY345899 (1 μM) for 14 days statistically significantly reduced cell colony formation (Supplementary Figure 6, A and B, available online). As expected, LY345899 treatment decreased cellular NADPH/NADP+ and GSH/GSSG levels (P < .01 for all) (Figure 7C, Supplementary Figure 6C, available online), increased cellular ROS levels, and caused more cell death in CRC cells, which could be rescued by adding NAC (P < .001 for all) (Figure 7C, Supplementary Figure 6, D and E, available online). However, addition of 5 mM formate to media did not rescue the cell apoptosis in these cells (Supplementary Figure 6E, available online), suggesting that the cell death induced by LY345899 treatment is likely distinct from any reduction in formate production but redox modification. Accordingly, LY345899 treatment for 48 hours obviously enhanced cell death under hypoxia or detached conditions (P ≤ .01 for all) (Figure 7, D and E). J Natl Cancer Inst. 2019 Jun; 111(6): 584–596. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6579745/

In vivo activity:

Importantly, LY345899 treatment showed potent antitumor activity in vivo in nude mice, which was evident by the reduced SW620 cell or PDX-based tumor growth and tumor weight (mean tumor weight = 1.83 [0.19] mg for vehicle-treated PDX group vs 0.74 [0.30] mg for LY345899-treated group, P < .001, and similar results were seen in the other groups with a P < .001) (Figure 7, F and G, Supplementary Figure 6F, available online). Immunohistochemical staining showed the treated tumor also displayed lower cell proliferation indices and higher cell apoptosis (Supplementary Figures 6G and 7H, available online). Additionally, no statistically significant weight loss or other signs of acute or delayed toxicity were observed in any of the mice during treatment (Supplementary Figure 6F, available online). It was also found that LY345899 treatment reduced mesenteric metastatic nodules in mice implanted with SW620 or PDX-based tissues into the cecum (P < .001 for untreated vs treated groups) (Figure 7I). These findings indicate that LY345899 displays therapeutic activity against CRC and warrants further clinical investigation for CRC treatment. J Natl Cancer Inst. 2019 Jun; 111(6): 584–596. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6579745/

	Solvent	mg/mL	mM
Solubility
	DMSO	125.0	265.16

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 471.43 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.

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

Formulation protocol:

1. Ju HQ, Lu YX, Chen DL, Zuo ZX, Liu ZX, Wu QN, Mo HY, Wang ZX, Wang DS, Pu HY, Zeng ZL, Li B, Xie D, Huang P, Hung MC, Chiao PJ, Xu RH. Modulation of Redox Homeostasis by Inhibition of MTHFD2 in Colorectal Cancer: Mechanisms and Therapeutic Implications. J Natl Cancer Inst. 2019 Jun 1;111(6):584-596. doi: 10.1093/jnci/djy160. PMID: 30534944; PMCID: PMC6579745.

In vitro protocol:

In vivo protocol:

1: Ju HQ, Lu YX, Chen DL, Zuo ZX, Liu ZX, Wu QN, Mo HY, Wang ZX, Wang DS, Pu HY, Zeng ZL, Li B, Xie D, Huang P, Hung MC, Chiao PJ, Xu RH. Modulation of Redox Homeostasis by Inhibition of MTHFD2 in Colorectal Cancer: Mechanisms and Therapeutic Implications. J Natl Cancer Inst. 2018 Dec 8. doi: 10.1093/jnci/djy160. [Epub ahead of print] PubMed PMID: 30534944.