Glasdegib (PF-04449913)
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MedKoo CAT#: 205582

CAS#: 1095173-27-5 (free base)

Description: Glasdegib, also known as PF-04449913, is an orally bioavailable small-molecule inhibitor of the Hedgehog (Hh) signaling pathway with potential antineoplastic activity. Hedgehog inhibitor PF-04449913 appears to inhibit Hh pathway signaling. The Hh signaling pathway plays an important role in cellular growth, differentiation and repair. Constitutive activation of Hh pathway signaling has been observed in various types of malignancies.


Chemical Structure

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Glasdegib (PF-04449913)
CAS# 1095173-27-5 (free base)

Theoretical Analysis

MedKoo Cat#: 205582
Name: Glasdegib (PF-04449913)
CAS#: 1095173-27-5 (free base)
Chemical Formula: C21H22N6O
Exact Mass: 374.18551
Molecular Weight: 374.44
Elemental Analysis: C, 67.36; H, 5.92; N, 22.44; O, 4.27

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500.0mg USD 2650.0 Same day
1.0g USD 3850.0 2 weeks
2.0g USD 6950.0 2 weeks
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Related CAS #: 1095173-27-5 (free base)   2030410-25-2 (maleate)   1095173-64-0 (HCl)   1352568-48-9 (2HCl)    

Synonym: PF04449913; PF-04449913; PF 04449913; PF4449913; PF-4449913; PF 4449913; Glasdegib.

IUPAC/Chemical Name: 1-((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)urea

InChi Key: SFNSLLSYNZWZQG-VQIMIIECSA-N

InChi Code: InChI=1S/C21H22N6O/c1-27-11-10-16(24-21(28)23-15-8-6-14(13-22)7-9-15)12-19(27)20-25-17-4-2-3-5-18(17)26-20/h2-9,16,19H,10-12H2,1H3,(H,25,26)(H2,23,24,28)/t16-,19-/m1/s1

SMILES Code: O=C(NC1=CC=C(C#N)C=C1)N[C@H]2C[C@H](C3=NC4=CC=CC=C4N3)N(C)CC2

Appearance: white 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: Glasdegib (PF-04449913) is a potent, and orally bioavailable Smoothened (Smo) inhibitor with IC50 of 5 nM.
In vitro activity: Glasdegib (PF-04449913) inhibits sonic hedgehog (Shh) stimulated luciferase expression in mouse embryonic fibroblasts with an IC50 of 6.8 nM; and significantly reduces medulloblastoma growth in a Ptch1+/-p53+/- allograft model at doses that decreased murine Shh target gene expression. In stromal co-culture experiments, FACS analysis demonstrates a significant reduction in BC LSC by Glasdegib (PF-04449913) when compared with normal progenitors. Importantly, human BC LSC engrafted RAG2-/-γC-/- mice treated daily with Glasdegib (PF-04449913) compared with vehicle treated controls have a significant spleen weight reduction (p=0.006). This reduction in leukemic burden corresponded with decreased GLI2 protein expression, as determined by both nanoproteomic analysis of FACS purified human progenitors and GLI2 confocal fluorescence microscopic analysis of splenic sections. Reference: J Transl Med. 2015 Mar 21;13:98. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25889765/
In vivo activity: Human BC LSC engrafted RAG2-/-γC-/- mice treated daily with Glasdegib (PF-04449913) compared with vehicle treated controls had a significant spleen weight reduction (p=0.006). When CD34+ cord blood engrafted NSG mice are treated with Glasdegib (PF-04449913), the frequency of human CD45+ cells, progenitors and both myeloid and lymphoid cell fate commitment remained comparable to vehicle treated controls indicating that unlike LSC, normal human HSC cell fate decisions are Hh pathway independent. These results highlight the important niche dependent effects of selective SMO inhibition that induce GLI2 downregulation in a cell type and context specific manner. Reference: J Transl Med. 2015 Mar 21;13:98. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25889765/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 74.0 197.63

Preparing Stock Solutions

The following data is based on the product molecular weight 374.44 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. Sadarangani A, Pineda G, Lennon KM, Chun HJ, Shih A, Schairer AE, Court AC, Goff DJ, Prashad SL, Geron I, Wall R, McPherson JD, Moore RA, Pu M, Bao L, Jackson-Fisher A, Munchhof M, VanArsdale T, Reya T, Morris SR, Minden MD, Messer K, Mikkola HK, Marra MA, Hudson TJ, Jamieson CH. GLI2 inhibition abrogates human leukemia stem cell dormancy. J Transl Med. 2015 Mar 21;13:98. doi: 10.1186/s12967-015-0453-9. PMID: 25889765; PMCID: PMC4414375.
In vivo protocol: 1. Sadarangani A, Pineda G, Lennon KM, Chun HJ, Shih A, Schairer AE, Court AC, Goff DJ, Prashad SL, Geron I, Wall R, McPherson JD, Moore RA, Pu M, Bao L, Jackson-Fisher A, Munchhof M, VanArsdale T, Reya T, Morris SR, Minden MD, Messer K, Mikkola HK, Marra MA, Hudson TJ, Jamieson CH. GLI2 inhibition abrogates human leukemia stem cell dormancy. J Transl Med. 2015 Mar 21;13:98. doi: 10.1186/s12967-015-0453-9. PMID: 25889765; PMCID: PMC4414375.

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1: Lin S, Shaik N, Martinelli G, Wagner AJ, Cortes J, Ruiz-Garcia A. Population Pharmacokinetics of Glasdegib in Patients With Advanced Hematologic Malignancies and Solid Tumors. J Clin Pharmacol. 2019 Nov 25. doi: 10.1002/jcph.1556. [Epub ahead of print] PubMed PMID: 31769065.

2: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Available from http://www.ncbi.nlm.nih.gov/books/NBK548156/ PubMed PMID: 31643486.

3: Goldsmith SR, Lovell AR, Schroeder MA. Glasdegib for the treatment of adult patients with newly diagnosed acute myeloid leukemia or high-grade myelodysplastic syndrome who are elderly or otherwise unfit for standard induction chemotherapy. Drugs Today (Barc). 2019 Sep;55(9):545-562. doi: 10.1358/dot.2019.55.9.3020160. PubMed PMID: 31584572.

4: Tremblay G, Westley T, Cappelleri JC, Arondekar B, Chan G, Bell TJ, Briggs A. Overall survival of glasdegib in combination with low-dose cytarabine, azacitidine, and decitabine among adult patients with previously untreated AML: comparative effectiveness using simulated treatment comparisons. Clinicoecon Outcomes Res. 2019 Sep 6;11:551-565. doi: 10.2147/CEOR.S203482. eCollection 2019. PubMed PMID: 31564931; PubMed Central PMCID: PMC6735653.

5: Cortes JE, Dombret H, Merchant A, Tauchi T, DiRienzo CG, Sleight B, Zhang X, Leip EP, Shaik N, Bell T, Chan G, Sekeres MA. Glasdegib plus intensive/nonintensive chemotherapy in untreated acute myeloid leukemia: BRIGHT AML 1019 Phase III trials. Future Oncol. 2019 Nov;15(31):3531-3545. doi: 10.2217/fon-2019-0373. Epub 2019 Sep 13. PubMed PMID: 31516032.

6: Wolska-Washer A, Robak T. Glasdegib in the treatment of acute myeloid leukemia. Future Oncol. 2019 Oct;15(28):3219-3232. doi: 10.2217/fon-2019-0171. Epub 2019 Aug 21. PubMed PMID: 31432695.

7: Fathi AT. Glasdegib with Low-Dose Cytarabine: A New Upfront Option for the Vulnerable AML Patient. Clin Cancer Res. 2019 Oct 15;25(20):6015-6017. doi: 10.1158/1078-0432.CCR-19-1986. Epub 2019 Jul 19. PubMed PMID: 31324656.

8: Norsworthy KJ, By K, Subramaniam S, Zhuang L, Del Valle PL, Przepiorka D, Shen YL, Sheth CM, Liu C, Leong R, Goldberg KB, Farrell AT, Pazdur R. FDA Approval Summary: Glasdegib for Newly Diagnosed Acute Myeloid Leukemia. Clin Cancer Res. 2019 Oct 15;25(20):6021-6025. doi: 10.1158/1078-0432.CCR-19-0365. Epub 2019 May 7. PubMed PMID: 31064779.

9: Sallman DA, Komrokji RS, Sweet KL, Mo Q, McGraw KL, Duong VH, Zhang L, Nardelli LA, Padron E, List AF, Lancet JE. A phase 2 trial of the oral smoothened inhibitor glasdegib in refractory myelodysplastic syndromes (MDS). Leuk Res. 2019 Jun;81:56-61. doi: 10.1016/j.leukres.2019.03.008. Epub 2019 Mar 30. PubMed PMID: 31030089.

10: Gerds AT, Tauchi T, Ritchie E, Deininger M, Jamieson C, Mesa R, Heaney M, Komatsu N, Minami H, Su Y, Shaik N, Zhang X, DiRienzo C, Zeremski M, Chan G, Talpaz M. Corrigendum to "Phase 1/2 trial of glasdegib in patients with primary or secondary myelofibrosis previously treated with ruxolitinib" [Leukemia Res. 79 (2019) 38-44]. Leuk Res. 2019 Jun;81:105. doi: 10.1016/j.leukres.2019.04.006. Epub 2019 Apr 24. PubMed PMID: 31029462.

11: Shaik N, Hee B, Liang Y, LaBadie RR. Absolute Oral Bioavailability of Glasdegib (PF-04449913), a Smoothened Inhibitor, in Randomized Healthy Volunteers. Clin Pharmacol Drug Dev. 2019 Oct;8(7):895-902. doi: 10.1002/cpdd.692. Epub 2019 Apr 12. PubMed PMID: 30977980; PubMed Central PMCID: PMC6850403.

12: Gerds AT, Tauchi T, Ritchie E, Deininger M, Jamieson C, Mesa R, Heaney M, Komatsu N, Minami H, Su Y, Shaik N, Zhang X, DiRienzo C, Zeremski M, Chan G, Talpaz M. Phase 1/2 trial of glasdegib in patients with primary or secondary myelofibrosis previously treated with ruxolitinib. Leuk Res. 2019 Apr;79:38-44. doi: 10.1016/j.leukres.2019.02.012. Epub 2019 Feb 28. Erratum in: Leuk Res. 2019 Jun;81:105. PubMed PMID: 30849661.

13: Hoy SM. Glasdegib: First Global Approval. Drugs. 2019 Feb;79(2):207-213. doi: 10.1007/s40265-018-1047-7. Review. PubMed PMID: 30666593.

14: Drugs and Lactation Database (LactMed) [Internet]. Bethesda (MD): National Library of Medicine (US); 2006-. Available from http://www.ncbi.nlm.nih.gov/books/NBK535600/ PubMed PMID: 30601609.

15: Cortes JE, Heidel FH, Hellmann A, Fiedler W, Smith BD, Robak T, Montesinos P, Pollyea DA, DesJardins P, Ottmann O, Ma WW, Shaik MN, Laird AD, Zeremski M, O'Connell A, Chan G, Heuser M. Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. Leukemia. 2019 Feb;33(2):379-389. doi: 10.1038/s41375-018-0312-9. Epub 2018 Dec 16. PubMed PMID: 30555165; PubMed Central PMCID: PMC6365492.

16: Shaik N, Hee B, Wei H, LaBadie RR. Evaluation of the effects of formulation, food, or a proton-pump inhibitor on the pharmacokinetics of glasdegib (PF-04449913) in healthy volunteers: a randomized phase I study. Cancer Chemother Pharmacol. 2019 Mar;83(3):463-472. doi: 10.1007/s00280-018-3748-8. Epub 2018 Dec 10. PubMed PMID: 30536154; PubMed Central PMCID: PMC6394474.

17: Cortes JE, Douglas Smith B, Wang ES, Merchant A, Oehler VG, Arellano M, DeAngelo DJ, Pollyea DA, Sekeres MA, Robak T, Ma WW, Zeremski M, Naveed Shaik M, Douglas Laird A, O'Connell A, Chan G, Schroeder MA. Glasdegib in combination with cytarabine and daunorubicin in patients with AML or high-risk MDS: Phase 2 study results. Am J Hematol. 2018 Nov;93(11):1301-1310. doi: 10.1002/ajh.25238. Epub 2018 Sep 9. PubMed PMID: 30074259; PubMed Central PMCID: PMC6221102.

18: Shaik MN, Hee B, Wei H, LaBadie RR. Evaluation of the effect of rifampin on the pharmacokinetics of the Smoothened inhibitor glasdegib in healthy volunteers. Br J Clin Pharmacol. 2018 Jun;84(6):1346-1353. doi: 10.1111/bcp.13568. Epub 2018 Apr 10. PubMed PMID: 29488303; PubMed Central PMCID: PMC5980541.

19: Savona MR, Pollyea DA, Stock W, Oehler VG, Schroeder MA, Lancet J, McCloskey J, Kantarjian HM, Ma WW, Shaik MN, Laird AD, Zeremski M, O'Connell A, Chan G, Cortes JE. Phase Ib Study of Glasdegib, a Hedgehog Pathway Inhibitor, in Combination with Standard Chemotherapy in Patients with AML or High-Risk MDS. Clin Cancer Res. 2018 May 15;24(10):2294-2303. doi: 10.1158/1078-0432.CCR-17-2824. Epub 2018 Feb 20. PubMed PMID: 29463550.

20: Giri N, Lam LH, LaBadie RR, Krzyzaniak JF, Jiang H, Hee B, Liang Y, Shaik MN. Evaluation of the effect of new formulation, food, or a proton pump inhibitor on the relative bioavailability of the smoothened inhibitor glasdegib (PF-04449913) in healthy volunteers. Cancer Chemother Pharmacol. 2017 Dec;80(6):1249-1260. doi: 10.1007/s00280-017-3472-9. Epub 2017 Oct 30. PubMed PMID: 29086063.



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