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.
Gedatolisib acts as a dual mTOR/PI3K inhibitor.[citation needed]
mTOR inhibitionedit
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 inhibitionedit
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]
^Dehnhardt CM, Venkatesan AM, Chen Z, Delos-Santos E, Ayral-Kaloustian S, Brooijmans N, Yu K, Hollander I, Feldberg L, Lucas J, Mallon R (August 2011). "Identification of 2-oxatriazines as highly potent pan-PI3K/mTOR dual inhibitors". Bioorganic & Medicinal Chemistry Letters. 21 (16): 4773–8. doi:10.1016/j.bmcl.2011.06.063. PMID 21763134.
^Sabatini DM (November 2017). "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. doi:10.1073/pnas.1716173114. PMC5692607. PMID 29078414.
^Tian T, Li X, Zhang J (February 2019). "mTOR Signaling in Cancer and mTOR Inhibitors in Solid Tumor Targeting Therapy". International Journal of Molecular Sciences. 20 (3): 755. doi:10.3390/ijms20030755. PMC6387042. PMID 30754640.
^Hua H, Kong Q, Zhang H, Wang J, Luo T, Jiang Y (July 2019). "Targeting mTOR for cancer therapy". Journal of Hematology & Oncology. 12 (1): 71. doi:10.1186/s13045-019-0754-1. PMC6612215. PMID 31277692.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^Vanhaesebroeck B, Perry MW, Brown JR, André F, Okkenhaug K (October 2021). "PI3K inhibitors are finally coming of age". Nature Reviews. Drug Discovery. 20 (10): 741–769. doi:10.1038/s41573-021-00209-1. PMC9297732. PMID 34127844. S2CID 235437841.
^Millis SZ, Ikeda S, Reddy S, Gatalica Z, Kurzrock R (December 2016). "Landscape of Phosphatidylinositol-3-Kinase Pathway Alterations Across 19 784 Diverse Solid Tumors". JAMA Oncology. 2 (12): 1565–1573. doi:10.1001/jamaoncol.2016.0891. PMID 27388585.
^Anderson EJ, Mollon LE, Dean JL, Warholak TL, Aizer A, Platt EA, Tang DH, Davis LE (2020). "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. doi:10.1155/2020/3759179. PMC7322582. 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
gedatolisib, 05212384, experimental, drug, treatment, cancer, development, celcuity, mechanism, action, accomplished, binding, different, p110, catalytic, subunit, isoforms, pi3k, kinase, site, mtor, clinical, dataother, namespf, 05212384, 587identifiersiupac,. 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 GedatolisibClinical dataOther namesPF 05212384 PKI 587IdentifiersIUPAC name 1 4 4 Dimethylamino piperidine 1 carbonyl phenyl 3 4 4 6 dimorpholin 4 yl 1 3 5 triazin 2 yl phenyl ureaCAS Number1197160 78 3PubChem CID44516953UNII96265TNH2RKEGGD10635CompTox Dashboard EPA DTXSID40152557Chemical and physical dataFormulaC 32H 41N 9O 4Molar mass615 739 g mol 13D model JSmol Interactive imageSMILES CN C C1CCN CC1 C O C2 CC C C C2 NC O NC3 CC C C C3 C4 NC NC N4 N5CCOCC5 N6CCOCC6InChI InChI 1S C32H41N9O4 c1 38 2 27 11 13 39 14 12 27 29 42 24 5 9 26 10 6 24 34 32 43 33 25 7 3 23 4 8 25 28 35 30 40 15 19 44 20 16 40 37 31 36 28 41 17 21 45 22 18 41 h3 10 27H 11 22H2 1 2H3 H2 33 34 43 Key DWZAEMINVBZMHQ UHFFFAOYSA NThe drug was originally developed by Wyeth which Pfizer acquired in 2009 Gedatolisib is under development for patients with and without PIK3CA mutations Contents 1 Mechanism of action 1 1 mTOR inhibition 1 2 PI3K inhibition 2 Clinical trials 3 ReferencesMechanism of action editGedatolisib acts as a dual mTOR PI3K inhibitor citation needed mTOR inhibition edit 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 edit 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 editA 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 edit Dehnhardt CM Venkatesan AM Chen Z Delos Santos E Ayral Kaloustian S Brooijmans N Yu K Hollander I Feldberg L Lucas J Mallon R August 2011 Identification of 2 oxatriazines as highly potent pan PI3K mTOR dual inhibitors Bioorganic amp Medicinal Chemistry Letters 21 16 4773 8 doi 10 1016 j bmcl 2011 06 063 PMID 21763134 Sabatini DM November 2017 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 doi 10 1073 pnas 1716173114 PMC 5692607 PMID 29078414 Tian T Li X Zhang J February 2019 mTOR Signaling in Cancer and mTOR Inhibitors in Solid Tumor Targeting Therapy International Journal of Molecular Sciences 20 3 755 doi 10 3390 ijms20030755 PMC 6387042 PMID 30754640 Hua H Kong Q Zhang H Wang J Luo T Jiang Y July 2019 Targeting mTOR for cancer therapy Journal of Hematology amp Oncology 12 1 71 doi 10 1186 s13045 019 0754 1 PMC 6612215 PMID 31277692 a href Template Cite journal html title Template Cite journal cite journal a CS1 maint unflagged free DOI link Vanhaesebroeck B Perry MW Brown JR Andre F Okkenhaug K October 2021 PI3K inhibitors are finally coming of age Nature Reviews Drug Discovery 20 10 741 769 doi 10 1038 s41573 021 00209 1 PMC 9297732 PMID 34127844 S2CID 235437841 Millis SZ Ikeda S Reddy S Gatalica Z Kurzrock R December 2016 Landscape of Phosphatidylinositol 3 Kinase Pathway Alterations Across 19 784 Diverse Solid Tumors JAMA Oncology 2 12 1565 1573 doi 10 1001 jamaoncol 2016 0891 PMID 27388585 Anderson EJ Mollon LE Dean JL Warholak TL Aizer A Platt EA Tang DH Davis LE 2020 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 doi 10 1155 2020 3759179 PMC 7322582 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 amp 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 nbsp This article incorporates public domain material from the United States Government Retrieved from https en wikipedia org w index php title Gedatolisib amp oldid 1170450642, wikipedia, wiki, book, books, library,
