PFK-158
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MedKoo CAT#: 206166

CAS#: 1462249-75-7

Description: PFK-158, also known as ACT-PFK-158, is an inhibitor of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFK-2/FBPase) isoform 3 (PFKFB3) with potential antineoplastic activity. Upon administration, PFKFB3 inhibitor PFK-158 binds to and inhibits the activity of PFKFB3, which leads to the inhibition of both the glycolytic pathway in and glucose uptake by cancer cells. This prevents the production of macromolecules and energy that causes the enhanced cellular proliferation in cancer cells as compared to that of normal, healthy cells. Depriving cancer cells of nutrients and energy leads to the inhibition of cancer cell growth.


Chemical Structure

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PFK-158
CAS# 1462249-75-7

Theoretical Analysis

MedKoo Cat#: 206166
Name: PFK-158
CAS#: 1462249-75-7
Chemical Formula: C18H11F3N2O
Exact Mass: 328.08
Molecular Weight: 328.290
Elemental Analysis: C, 65.85; H, 3.38; F, 17.36; N, 8.53; O, 4.87

Price and Availability

Size Price Availability Quantity
10mg USD 90 Ready to ship
25mg USD 150 Ready to ship
50mg USD 250 Ready to ship
100mg USD 450 Ready to ship
200mg USD 750 Ready to ship
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Synonym: PFK158; PFK 158; PFK158; ACTPFK158.

IUPAC/Chemical Name: (E)-1-(pyridin-4-yl)-3-(7-(trifluoromethyl)quinolin-2-yl)prop-2-en-1-one

InChi Key: IAJOMYABKVAZCN-AATRIKPKSA-N

InChi Code: InChI=1S/C18H11F3N2O/c19-18(20,21)14-3-1-12-2-4-15(23-16(12)11-14)5-6-17(24)13-7-9-22-10-8-13/h1-11H/b6-5+

SMILES Code: O=C(C1=CC=NC=C1)/C=C/C2=NC3=CC(C(F)(F)F)=CC=C3C=C2

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, 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

More Info: The PFKFB enzymes (PFKFB 1- 4) synthesize fructose-2,6-bisphosphate (F2,6BP) which activates 6-phosphofructo-l- kinase (PFK-1), an essential control point in the glycolytic pathway. Neoplastic cells preferentially utilize glycolysis to satisfy their increased needs for energy and biosynthetic precursors. Malignant tumor cells have glycolytic rates that are up to 200 times higher than those of their normal tissues of origin. One cancer attack strategy has been to treat cancer by starving cancerous cells in various ways. Reducing or blocking the enhanced glycolytic flux mechanism present in cancer cells has stimulated recent interest. Despite greater understanding and pharmaceutical advances in the diagnosis and treatment of cancer, it is still estimated that nearly 13% of all human deaths last year were due to cancer. Thus, there remains a need for safe and effective anti-cancer therapeutics, particularly those which target neoplastic cells via mechanisms such as glycolytic flux, which are over-expressed in cancer cells. (http://www.google.com/patents/WO2013148228A1?cl=en)       

Biological target: PFK-158 is a potent and selective PFKFB3 inhibitor that reduces glucose uptake, ATP production, lactate release, and induces apoptosis and autophagy in cancer cells. PFK-158 has an IC50 value of 137 nM.
In vitro activity: Since elevated glucose utilization in cancer supports lipogenesis at multiple levels13 and considering that it could be another contributing factor toward chemoresistance, it was checked whether PFK158 treatment could modulate lipid pathways. Results showed that the C13 and HeyA8MDR cells had more LDs compared to the chemosensitive cells (Fig.4 a and b) and PFK158 treatment significantly reduced the number of LDs in these cells (Fig4 c and d). Of interest, genetic downregulation of PFKFB3 in C13 and HeyA8MDR cells (Fig.4 e and g) also resulted in a reduction of LDs. The data indicates that PFK158 has synergistic antiproliferative effects in vitro when combined with cisplatin in C13 and HeyA8MDR cells compared to OV2008 and HeyA8, respectively (Fig. S3A‐C and E‐G, Supporting Information). PFK158 treatment induces lipophagy and also sensitizes chemoresistant cells to chemotherapy‐induced cytotoxicity both in vitro and in vivo. Importantly, this data also showed that inhibiting autophagy with BafA reverses the PFK158‐induced chemosensitivity to carboplatin more in the resistant than the sensitive cells. In conclusion, this is one of the first studies to show that PFK158, a specific inhibitor of PFKFB3, simultaneously targets both the glycolytic and lipogenic pathways, two pathways that are very active in cancer, and promotes lipophagy to inhibit tumor growth. Int J Cancer. 2019 Jan 1;144(1):178-189. https://pubmed.ncbi.nlm.nih.gov/30226266/
In vivo activity: PFK158 (Fig. (Fig.1b) obtained on an MTA from Gossamer Bio (San Diego, CA) was dissolved in 40% solution of Captisol in ddH2O for in vivo studies. To further investigate the activity of PFK158 alone and/or in combination with carboplatin (CBP) in an MPM xenograft nude mouse model, EMMeso cells were implanted subcutaneously in nude mice (Fig. S9A). A noticeable reduction in tumor burden (Fig. S9B and Fig.7a, tumor growth (Fig.7b), tumor volume (Fig.7c), and tumor weight (Fig.7d) were observed in both in PFK158 alone and in combination treatment. It was also observed that the tumor burden in PFK158-treated mice was significantly (P < 0.0002) less than the one in the vehicle-treated controls. However, the data also showed that the PFK158 alone was profoundly effective as it was in combination with CBP treatment in reducing pleural mesothelioma progression compared to CBP single treatment group Together the in vivo data revealed that PFK158-mediated inhibition of tumorigenesis occurs through methuosis and ER stress to reduce the tumor burden. Finally, PFK158 alone and in combination with carboplatin-inhibited tumorigenesis of EMMeso xenografts in vivo. Since most cancer cells exhibit an increased glycolytic rate, these results provide evidence for PFK158, in combination with standard chemotherapy, may have a potential in the treatment of MPM. This is the first study to establish that inhibition of PFKFB3 with a small molecule antagonist, PFK158; can introduce glycolytic assault which simultaneously triggers ER stress and methuosis and eventually suppress MPM cell growth both in vitro and in vivo (Fig.88). Cell Death Dis. 2019 Oct; 10(10): 725.Published online 2019 Sep 27. doi: 10.1038/s41419-019-1916-3 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764980/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 14.0 42.60

Preparing Stock Solutions

The following data is based on the product molecular weight 328.29 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
Formulation protocol: 1. Mondal S, Roy D, Sarkar Bhattacharya S, Jin L, Jung D, Zhang S, Kalogera E, Staub J, Wang Y, Xuyang W, Khurana A, Chien J, Telang S, Chesney J, Tapolsky G, Petras D, Shridhar V. Therapeutic targeting of PFKFB3 with a novel glycolytic inhibitor PFK158 promotes lipophagy and chemosensitivity in gynecologic cancers. Int J Cancer. 2019 Jan 1;144(1):178-189. doi: 10.1002/ijc.31868. Epub 2018 Oct 30. Erratum in: Int J Cancer. 2019 Jul 15;145(2):E13. PMID: 30226266; PMCID: PMC6261695. 2. Sarkar Bhattacharya S, Thirusangu P, Jin L, Roy D, Jung D, Xiao Y, Staub J, Roy B, Molina JR, Shridhar V. PFKFB3 inhibition reprograms malignant pleural mesothelioma to nutrient stress-induced macropinocytosis and ER stress as independent binary adaptive responses. Cell Death Dis. 2019 Sep 27;10(10):725. doi: 10.1038/s41419-019-1916-3. PMID: 31562297; PMCID: PMC6764980. 3. . Mondal S, Roy D, Sarkar Bhattacharya S, Jin L, Jung D, Zhang S, Kalogera E, Staub J, Wang Y, Xuyang W, Khurana A, Chien J, Telang S, Chesney J, Tapolsky G, Petras D, Shridhar V. Therapeutic targeting of PFKFB3 with a novel glycolytic inhibitor PFK158 promotes lipophagy and chemosensitivity in gynecologic cancers. Int J Cancer. 2019 Jan 1;144(1):178-189. doi: 10.1002/ijc.31868. Epub 2018 Oct 30. Erratum in: Int J Cancer. 2019 Jul 15;145(2):E13. PMID: 30226266; PMCID: PMC6261695. 4. Sarkar Bhattacharya S, Thirusangu P, Jin L, Roy D, Jung D, Xiao Y, Staub J, Roy B, Molina JR, Shridhar V. PFKFB3 inhibition reprograms malignant pleural mesothelioma to nutrient stress-induced macropinocytosis and ER stress as independent binary adaptive responses. Cell Death Dis. 2019 Sep 27;10(10):725. doi: 10.1038/s41419-019-1916-3. PMID: 31562297; PMCID: PMC6764980.
In vitro protocol: 1. Mondal S, Roy D, Sarkar Bhattacharya S, Jin L, Jung D, Zhang S, Kalogera E, Staub J, Wang Y, Xuyang W, Khurana A, Chien J, Telang S, Chesney J, Tapolsky G, Petras D, Shridhar V. Therapeutic targeting of PFKFB3 with a novel glycolytic inhibitor PFK158 promotes lipophagy and chemosensitivity in gynecologic cancers. Int J Cancer. 2019 Jan 1;144(1):178-189. doi: 10.1002/ijc.31868. Epub 2018 Oct 30. Erratum in: Int J Cancer. 2019 Jul 15;145(2):E13. PMID: 30226266; PMCID: PMC6261695. 2. Sarkar Bhattacharya S, Thirusangu P, Jin L, Roy D, Jung D, Xiao Y, Staub J, Roy B, Molina JR, Shridhar V. PFKFB3 inhibition reprograms malignant pleural mesothelioma to nutrient stress-induced macropinocytosis and ER stress as independent binary adaptive responses. Cell Death Dis. 2019 Sep 27;10(10):725. doi: 10.1038/s41419-019-1916-3. PMID: 31562297; PMCID: PMC6764980.
In vivo protocol: 1. Mondal S, Roy D, Sarkar Bhattacharya S, Jin L, Jung D, Zhang S, Kalogera E, Staub J, Wang Y, Xuyang W, Khurana A, Chien J, Telang S, Chesney J, Tapolsky G, Petras D, Shridhar V. Therapeutic targeting of PFKFB3 with a novel glycolytic inhibitor PFK158 promotes lipophagy and chemosensitivity in gynecologic cancers. Int J Cancer. 2019 Jan 1;144(1):178-189. doi: 10.1002/ijc.31868. Epub 2018 Oct 30. Erratum in: Int J Cancer. 2019 Jul 15;145(2):E13. PMID: 30226266; PMCID: PMC6261695. 2. Sarkar Bhattacharya S, Thirusangu P, Jin L, Roy D, Jung D, Xiao Y, Staub J, Roy B, Molina JR, Shridhar V. PFKFB3 inhibition reprograms malignant pleural mesothelioma to nutrient stress-induced macropinocytosis and ER stress as independent binary adaptive responses. Cell Death Dis. 2019 Sep 27;10(10):725. doi: 10.1038/s41419-019-1916-3. PMID: 31562297; PMCID: PMC6764980.

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 1: Zhang Y, Wang X, Li X, Dong L, Hu X, Nie T, Lu Y, Lu X, Pang J, Li G, Yang X,
Li C, You X. Synergistic Effect of Colistin Combined with PFK-158 against
Colistin-Resistant Enterobacteriaceae. Antimicrob Agents Chemother. 2019 Jun
24;63(7). pii: e00271-19. doi: 10.1128/AAC.00271-19. Print 2019 Jul. PubMed PMID:
30988150; PubMed Central PMCID: PMC6591609.

2: Mondal S, Roy D, Sarkar Bhattacharya S, Jin L, Jung D, Zhang S, Kalogera E,
Staub J, Wang Y, Xuyang W, Khurana A, Chien J, Telang S, Chesney J, Tapolsky G,
Petras D, Shridhar V. Therapeutic targeting of PFKFB3 with a novel glycolytic
inhibitor PFK158 promotes lipophagy and chemosensitivity in gynecologic cancers.
Int J Cancer. 2019 Jan 1;144(1):178-189. doi: 10.1002/ijc.31868. Epub 2018 Oct
30. Erratum in: Int J Cancer. 2019 Jul 15;145(2):E13. PubMed PMID: 30226266;
PubMed Central PMCID: PMC6261695.