Gedatolisib

Gedatolisib acts as a dual mTOR/PI3K inhibitor.{{cn|date=February 2023}}

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.  In cancer, dysfunctional mTOR signaling leads to various constitutive activities of both mTOR-involved complexes, making mTOR an important therapeutic target for cancer therapy. Gedatolisib also binds to mTOR to inhibit its activity.{{cn|date=February 2023}}

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.  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. Gedatolisib binds to all PI3K catalytic subunit isoforms involved in oncogenic signaling approximately equally.

A number of early phase clinical trials of gedatolisib for treatment of endometrial cancer, colorectal cancer, acute myeloid leukemia have been conducted.{{ClinicalTrialsGov|NCT01420081|A Study Of Two Dual PI3K/mTOR Inhibitors, PF-04691502 And PF-05212384 In Patients With Recurrent Endometrial Cancer}}{{ClinicalTrialsGov|NCT01925274|A Study Of PF-05212384 Plus Irinotecan Vs Cetuximab Plus Irinotecan In Patients With KRAS And NRAS Wild Type Metastatic Colorectal Cancer}}{{ClinicalTrialsGov|NCT02438761|PF-05212384 (PKI-587) for t-AML/MDS or de Novo Relapsed or Refractory Acute Myeloid Leukemia (AML)}}

Current clinical trials are focused on breast cancer,

{{Reflist|refs=

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{{cite journal | vauthors = Millis SZ, Ikeda S, Reddy S, Gatalica Z, Kurzrock R | title = Landscape of Phosphatidylinositol-3-Kinase Pathway Alterations Across 19 784 Diverse Solid Tumors | journal = JAMA Oncology | volume = 2 | issue = 12 | pages = 1565–1573 | date = December 2016 | pmid = 27388585 | doi = 10.1001/jamaoncol.2016.0891 | doi-access = free }}

{{cite journal | vauthors = Sabatini DM | title = Twenty-five years of mTOR: Uncovering the link from nutrients to growth | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 114 | issue = 45 | pages = 11818–11825 | date = November 2017 | pmid = 29078414 | pmc = 5692607 | doi = 10.1073/pnas.1716173114 | doi-access = free | bibcode = 2017PNAS..11411818S }}

{{cite journal | vauthors = Tian T, Li X, Zhang J | title = mTOR Signaling in Cancer and mTOR Inhibitors in Solid Tumor Targeting Therapy | journal = International Journal of Molecular Sciences | volume = 20 | issue = 3 | date = February 2019 | page = 755 | pmid = 30754640 | pmc = 6387042 | doi = 10.3390/ijms20030755 | doi-access = free }}

{{cite journal | vauthors = Vanhaesebroeck B, Perry MW, Brown JR, André F, Okkenhaug K | title = PI3K inhibitors are finally coming of age | journal = Nature Reviews. Drug Discovery | volume = 20 | issue = 10 | pages = 741–769 | date = October 2021 | pmid = 34127844 | doi = 10.1038/s41573-021-00209-1 | pmc = 9297732 | s2cid = 235437841 }}

{{ClinicalTrialsGov|NCT03698383|Phase II Study of Herzuma® Plus Gedatolisib in Patients With HER-2 Positive Metastatic Breast Cancer}}

{{ClinicalTrialsGov|NCT03911973|Gedatolisib Plus Talazoparib in Advanced Triple Negative or BRCA1/2 Positive, HER2 Negative Breast Cancers}}

{{ClinicalTrialsGov|NCT03065062|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}}

{{ClinicalTrialsGov|NCT02626507|Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With ER+/HER2- Breast Cancer}}

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Category:Experimental cancer drugs

Category:Drugs developed by Pfizer

Category:4-Morpholinyl compounds

Category:Triazines

Category:Ureas

Category:Benzamides

Category:Phosphoinositide 3-kinase inhibitors