Chemistry:Gedatolisib
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| Other names | PF-05212384;PKI-587 |
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| Formula | C32H41N9O4 |
| Molar mass | 615.739 g·mol−1 |
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Gedatolisib (PF-05212384) is an experimental drug for treatment of cancer in development by Celcuity, Inc. The mechanism of action is accomplished by binding the different p110 catalytic subunit isoforms of PI3K and the kinase site of mTOR.[1]
The drug was originally developed by Wyeth, which Pfizer acquired in 2009. Gedatolisib is under development for patients with and without PIK3CA mutations.
Mechanism of action
Gedatolisib acts as a dual mTOR/PI3K inhibitor.[citation needed]
mTOR inhibition
mTOR is a downstream effector of PI3K and is also independently regulated by hormones, growth factors, and nutrients. mTOR protein is found in two functionally distinct protein assemblies: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTOR signaling serves as a central regulator of cell metabolism, growth, proliferation, and survival.[2] In cancer, dysfunctional mTOR signaling leads to various constitutive activities of both mTOR-involved complexes, making mTOR an important therapeutic target for cancer therapy.[3][4] Gedatolisib also binds to mTOR to inhibit its activity.[citation needed]
PI3K inhibition
Activation of the PI3K/mTOR pathway has been implicated in a wide variety of human cancers including carcinomas of the breast, prostate, lung, endometrial, colon, and ovary, among others. Each of the four catalytic isoforms of class I PI3K preferentially mediate signal transduction and tumor cell survival based on the type of malignancy and the genetic or epigenetic alterations an individual patient harbors. Activities associated with PI3K involve the regulation of diverse cellular processes, including cell proliferation, survival, cytoskeletal organization, and glucose transport and utilization. Over activation of the PI3K pathway is frequently present in human malignancies and plays a key role in cancer progression.[5] Due to the multiple sub-cellular locations, activities, and importance of the different PI3K isoforms and complexes in regulating cancer cell proliferation, complete control of the PI3K pathway activity is an important target for efficacious cancer therapy.[6] Gedatolisib binds to all PI3K catalytic subunit isoforms involved in oncogenic signaling approximately equally.[7]
Clinical trials
A number of early phase clinical trials of gedatolisib for treatment of endometrial cancer, colorectal cancer, acute myeloid leukemia have been conducted.[8][9][10]
Current clinical trials are focused on breast cancer,[11][12][13][14]
References
- ↑ "Identification of 2-oxatriazines as highly potent pan-PI3K/mTOR dual inhibitors". Bioorganic & Medicinal Chemistry Letters 21 (16): 4773–8. August 2011. doi:10.1016/j.bmcl.2011.06.063. PMID 21763134.
- ↑ "Twenty-five years of mTOR: Uncovering the link from nutrients to growth". Proceedings of the National Academy of Sciences of the United States of America 114 (45): 11818–11825. November 2017. doi:10.1073/pnas.1716173114. PMID 29078414. Bibcode: 2017PNAS..11411818S.
- ↑ "mTOR Signaling in Cancer and mTOR Inhibitors in Solid Tumor Targeting Therapy". International Journal of Molecular Sciences 20 (3): 755. February 2019. doi:10.3390/ijms20030755. PMID 30754640.
- ↑ "Targeting mTOR for cancer therapy". Journal of Hematology & Oncology 12 (1): 71. July 2019. doi:10.1186/s13045-019-0754-1. PMID 31277692.
- ↑ "PI3K inhibitors are finally coming of age". Nature Reviews. Drug Discovery 20 (10): 741–769. October 2021. doi:10.1038/s41573-021-00209-1. PMID 34127844.
- ↑ "Landscape of Phosphatidylinositol-3-Kinase Pathway Alterations Across 19 784 Diverse Solid Tumors". JAMA Oncology 2 (12): 1565–1573. December 2016. doi:10.1001/jamaoncol.2016.0891. PMID 27388585.
- ↑ "A Systematic Review of the Prevalence and Diagnostic Workup of PIK3CA Mutations in HR+/HER2- Metastatic Breast Cancer". International Journal of Breast Cancer 2020: 3759179. 2020. doi:10.1155/2020/3759179. PMID 32637176.
- ↑ Clinical trial number NCT01420081 for "A Study Of Two Dual PI3K/mTOR Inhibitors, PF-04691502 And PF-05212384 In Patients With Recurrent Endometrial Cancer" at ClinicalTrials.gov
- ↑ Clinical trial number NCT01925274 for "A Study Of PF-05212384 Plus Irinotecan Vs Cetuximab Plus Irinotecan In Patients With KRAS And NRAS Wild Type Metastatic Colorectal Cancer" at ClinicalTrials.gov
- ↑ Clinical trial number NCT02438761 for "PF-05212384 (PKI-587) for t-AML/MDS or de Novo Relapsed or Refractory Acute Myeloid Leukemia (AML)" at ClinicalTrials.gov
- ↑ Clinical trial number NCT03698383 for "Phase II Study of Herzuma® Plus Gedatolisib in Patients With HER-2 Positive Metastatic Breast Cancer" at ClinicalTrials.gov
- ↑ Clinical trial number NCT03911973 for "Gedatolisib Plus Talazoparib in Advanced Triple Negative or BRCA1/2 Positive, HER2 Negative Breast Cancers" at ClinicalTrials.gov
- ↑ Clinical trial number NCT03065062 for "Study of the CDK4/6 Inhibitor Palbociclib (PD-0332991) in Combination With the PI3K/mTOR Inhibitor Gedatolisib (PF-05212384) for Patients With Advanced Squamous Cell Lung, Pancreatic, Head & Neck and Other Solid Tumors" at ClinicalTrials.gov
- ↑ Clinical trial number NCT02626507 for "Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With ER+/HER2- Breast Cancer" at ClinicalTrials.gov
This article incorporates public domain material from websites or documents of the United States Government.
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