PF-5274857 free base | CAS#1373615-35-0 | 613439-62-5 | hedgehog inhibitor

MedKoo Cat#: 406786 | Name: PF-5274857 freebase

Description:

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

PF-5274857 is a potent, orally active and selective hedgehog (Hh) signaling pathway inhibitor with an IC50 of 5.8 nM and a Ki of 4.6 nM. PF-5274857 was found to effectively penetrate the blood-brain barrier and inhibit Smo activity in the brain of primary medulloblastoma mice, resulting in improved animal survival rates. PF-5274857 was orally available and metabolically stable in vivo. PF-5274857 is a potentially attractive clinical candidate for the treatment of tumor types including brain tumors and brain metastasis driven by an activated Hh pathway.

Chemical Structure

PF-5274857 freebase

CAS#1373615-35-0 (free base)

Theoretical Analysis

MedKoo Cat#: 406786

Name: PF-5274857 freebase

CAS#: 1373615-35-0 (free base)

Chemical Formula: C20H25ClN4O3S

Exact Mass: 436.1336

Molecular Weight: 436.96

Elemental Analysis: C, 54.98; H, 5.77; Cl, 8.11; N, 12.82; O, 10.98; S, 7.34

Price and Availability

Size	Price	Availability
10mg	USD 150.00	Ready to ship
25mg	USD 250.00	Ready to ship
50mg	USD 450.00	Ready to ship
100mg	USD 750.00	Ready to ship
200mg	USD 1,250.00	Ready to ship
500mg	USD 1,950.00	Ready to ship
1g	USD 2,950.00	Ready to ship
2g	USD 4,650.00	Ready to ship

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Related CAS #

1613439-62-5 (HCl) 1373615-35-0 (free base) PF-5274857 mseylate

Synonym

PF-5274857; PF 5274857; PF5274857.

IUPAC/Chemical Name

1-(4-(5'-chloro-3,5-dimethyl-[2,4'-bipyridin]-2'-yl)piperazin-1-yl)-3-(methylsulfonyl)propan-1-one

InChi Key

BBVNTTZIOTWDSV-UHFFFAOYSA-N

InChi Code

InChI=1S/C20H25ClN4O3S/c1-14-10-15(2)20(23-12-14)16-11-18(22-13-17(16)21)24-5-7-25(8-6-24)19(26)4-9-29(3,27)28/h10-13H,4-9H2,1-3H3

SMILES Code

O=C(N1CCN(C2=NC=C(Cl)C(C3=NC=C(C)C=C3C)=C2)CC1)CCS(=O)(C)=O

Appearance

Light yellow to 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

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

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#C9R09B11

QC Data

View QC data: current batch, Lot#C9R09B11

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

PF-5274857 is a potent, selective, and brain-penetrant antagonist of Smo, with an IC50 of 5.8 nM and Ki of 4.6 nM.

In vitro activity:

The purpose of this study was to explore the effects of the Smoothened (Smo) inhibitor PF-5274857 on cigarette smoke (CS)-induced epithelial-mesenchymal transition (EMT) and apply a new idea fororal squamous cell carcinoma (OSCC) treatment. Beas-2b cells were used to investigate the CS-induced EMT. Both pretreat and post-treat were performed in the study. In pretreat group, after being pretreated with 3 μmol/L PF-5274857 for 2 h, cells were cultured with CS for 8 d; In post-treat group, cells were treated by 3 μmol/L PF-5274857 for 4 d after CS culture. Pretreat Beas-2b cells with PF-5274857 for 2 h can prevent the CS-induced EMT for epithelial and mesenchymal markers, as well as migration capacity. Up regulated E-cadherin and down regulated vimentin and α-SMA were observed by Western blot. Furthermore Beas-2b cells induced by CS that underwent EMT showed increased E-cadherin and decreased vimentin and α-SMA after treatment with PF-5274857 for 4 d. Importantly, the elevated migration capacity level was also decreased. The Smo inhibitor PF-5274857 has both preventive effect and therapeutic potential against CS-induced EMT. Sichuan Da Xue Xue Bao Yi Xue Ban. 2016 Jul;47(4):485-490. https://pubmed.ncbi.nlm.nih.gov/28591947/

In vivo activity:

The in vivo efficacy of PF-5274857 was evaluated in Ptch+/−p53+/− medulloblastoma allograft mice. PF-5274857 showed significant dose-dependent TGI and induced tumor regression at high doses (≥10 mg/kg) after 6 days of treatment (Fig. 2A). On day 6, the calculated percentage of TGI was 39% ± 8% (P = 0.4), 80% ± 34% (P = 0.1), 119% ± 24% (P = 0.003), and 133% ± 32% (P = 0.002) at 1, 5, 10, and 30 mg/kg of PF-5274857, respectively. No body weight loss or other signs of illness were observed over the course of the study (Fig. 2B). The effects of PF-5274857 on Hh pathway genes Gli1, Gli2, Ptch1, Ptch2, and Smo were measured in both tumor and skin in Ptch+/−p53−/− medulloblastoma allograft mice in a single-dose study. As shown in Fig. 3A, in tumor tissue, PF-5274857 downregulated Gli1, Gli2, Ptch1, and Ptch2 gene expression levels to various degrees with maximal effects being achieved between 6 and 12 hours postdose, whereas it had little effect on Smo levels. Taken together, the preclinical data suggest that PF-5274857 is a potentially attractive clinical candidate for treating tumor types driven by an activated Hh pathway including brain tumors and brainmetastasized tumors. Mol Cancer Ther. 2012 Jan;11(1):57-65. https://mct.aacrjournals.org/content/11/1/57.long

	Solvent	mg/mL	mM	comments
Solubility
	DMSO	50.0	114.40

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 436.96 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. Rohner A, Spilker ME, Lam JL, Pascual B, Bartkowski D, Li QJ, Yang AH, Stevens G, Xu M, Wells PA, Planken S, Nair S, Sun S. Effective targeting of Hedgehog signaling in a medulloblastoma model with PF-5274857, a potent and selective Smoothened antagonist that penetrates the blood-brain barrier. Mol Cancer Ther. 2012 Jan;11(1):57-65. doi: 10.1158/1535-7163.MCT-11-0691. Epub 2011 Nov 14. PMID: 22084163. 2. Lauressergues E, Heusler P, Lestienne F, Troulier D, Rauly-Lestienne I, Tourette A, Ailhaud MC, Cathala C, Tardif S, DenaisLaliève D, Calmettes MT, Degryse AD, Dumoulin A, De Vries L, Cussac D. Pharmacological evaluation of a series of smoothened antagonists in signaling pathways and after topical application in a depilated mouse model. Pharmacol Res Perspect. 2016 Mar 4;4(2):e00214. doi: 10.1002/prp2.214. PMID: 27069629; PMCID: PMC4804317. 3. Zhou WJ, Chen J, Feng Y, Fan YP, Li Q, Fu J, Zhang P. [Inhibition of Cigarettes Smoke-induced Epithelial to Mesenchymal Transition by the SMO Inhibitor PF-5274857 in Beas-2b Epithelial Cells]. Sichuan Da Xue Xue Bao Yi Xue Ban. 2016 Jul;47(4):485490. Chinese. PMID: 28591947. 4. Lauressergues E, Heusler P, Lestienne F, Troulier D, Rauly-Lestienne I, Tourette A, Ailhaud MC, Cathala C, Tardif S, DenaisLaliève D, Calmettes MT, Degryse AD, Dumoulin A, De Vries L, Cussac D. Pharmacological evaluation of a series of smoothened antagonists in signaling pathways and after topical application in a depilated mouse model. Pharmacol Res Perspect. 2016 Mar 4;4(2):e00214. doi: 10.1002/prp2.214. PMID: 27069629; PMCID: PMC4804317.

In vitro protocol:

1. Zhou WJ, Chen J, Feng Y, Fan YP, Li Q, Fu J, Zhang P. [Inhibition of Cigarettes Smoke-induced Epithelial to Mesenchymal Transition by the SMO Inhibitor PF-5274857 in Beas-2b Epithelial Cells]. Sichuan Da Xue Xue Bao Yi Xue Ban. 2016 Jul;47(4):485490. Chinese. PMID: 28591947. 2. Lauressergues E, Heusler P, Lestienne F, Troulier D, Rauly-Lestienne I, Tourette A, Ailhaud MC, Cathala C, Tardif S, DenaisLaliève D, Calmettes MT, Degryse AD, Dumoulin A, De Vries L, Cussac D. Pharmacological evaluation of a series of smoothened antagonists in signaling pathways and after topical application in a depilated mouse model. Pharmacol Res Perspect. 2016 Mar 4;4(2):e00214. doi: 10.1002/prp2.214. PMID: 27069629; PMCID: PMC4804317.

In vivo protocol:

1: Zhou WJ, Chen J, Feng Y, Fan YP, Li Q, Fu J, Zhang P. [Inhibition of Cigarettes Smoke-induced Epithelial to Mesenchymal Transition by the SMO Inhibitor PF-5274857 in Beas-2b Epithelial Cells]. Sichuan Da Xue Xue Bao Yi Xue Ban. 2016 Jul;47(4):485-490. Chinese. PubMed PMID: 28591947. 2: Lauressergues E, Heusler P, Lestienne F, Troulier D, Rauly-Lestienne I, Tourette A, Ailhaud MC, Cathala C, Tardif S, Denais-Laliève D, Calmettes MT, Degryse AD, Dumoulin A, De Vries L, Cussac D. Pharmacological evaluation of a series of smoothened antagonists in signaling pathways and after topical application in a depilated mouse model. Pharmacol Res Perspect. 2016 Mar 4;4(2):e00214. doi: 10.1002/prp2.214. eCollection 2016 Apr. PubMed PMID: 27069629; PubMed Central PMCID: PMC4804317. 3: Rohner A, Spilker ME, Lam JL, Pascual B, Bartkowski D, Li QJ, Yang AH, Stevens G, Xu M, Wells PA, Planken S, Nair S, Sun S. Effective targeting of Hedgehog signaling in a medulloblastoma model with PF-5274857, a potent and selective Smoothened antagonist that penetrates the blood-brain barrier. Mol Cancer Ther. 2012 Jan;11(1):57-65. doi: 10.1158/1535-7163.MCT-11-0691. Epub 2011 Nov 14. PubMed PMID: 22084163. Liu Y, Yuan Q, Wang Z, Ding L, Kong N, Liu J, Hu Y, Zhang Y, Li C, Yan G, Jiang Y, Sun H. A high level of KLF12 causes folic acid-resistant neural tube defects by activating the Shh signaling pathway in mice†. Biol Reprod. 2021 Oct 11;105(4):837-845. doi: 10.1093/biolre/ioab111. PMID: 34104947.