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From Wikipedia, the free encyclopedia

Gedatolisib
Clinical data
Trade namesRevtorpyk
Other namesPF-05212384; PKI-587
AHFS/Drugs.comrevtorpyk
License data
Routes of
administration		Intravenous infusion
Drug classAntineoplastic
ATC code
  • None
Legal status
Legal status
Identifiers
  • 1-[4-[4-(Dimethylamino)piperidine-1-carbonyl]phenyl]-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC32H41N9O4
Molar mass615.739 g·mol−1
3D model (JSmol)
  • CN(C)C1CCN(CC1)C(=O)C2=CC=C(C=C2)NC(=O)NC3=CC=C(C=C3)C4=NC(=NC(=N4)N5CCOCC5)N6CCOCC6
  • 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-N

Gedatolisib, sold under the brand name Revtorpyk, is an anti-cancer drug used for the treatment of breast cancer.[1] It is under development by Celcuity, Inc. Gedatolisib is a kinase inhibitor.[1] The mechanism of action is accomplished by binding the different p110 catalytic subunit isoforms of PI3K and the kinase site of mTOR.[2] Gedatolisib is administered by intravenous infusion.[1]

Gedatolisib was approved for medical use in the United States in July 2026.[1][3]

Medical uses

[edit]

Gedatolisib is indicated in combination with fulvestrant, with or without palbociclib, for the treatment of adults with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer without a PIK3CA mutation detected following progression on or after treatment with at least one line of endocrine therapy in the metastatic setting.[1]

Adverse effects

[edit]

The US prescription label includes warnings and precautions for stomatitis, dermatologic adverse reactions, hyperglycemia, and embryo-fetal toxicity.[3]

Mechanism of action

[edit]

Gedatolisib acts as a dual mTOR/PI3K inhibitor.[1]

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.[4]  In cancer, dysfunctional mTOR signaling leads to various constitutive activities of both mTOR-involved complexes, making mTOR an important therapeutic target for cancer therapy.[5][6] Gedatolisib also binds to mTOR to inhibit its activity.[1]

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.[7]  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.[8] Gedatolisib binds to all PI3K catalytic subunit isoforms involved in oncogenic signaling approximately equally.[9]

History

[edit]

Efficacy was evaluated in study 1 of VIKTORIA-1 (NCT05501886), an open-label, randomized, multi-center trial that enrolled 392 adults with locally advanced (inoperable) or metastatic hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer.[3] Participants were randomized (1:1:1) to receive either gedatolisib in combination with fulvestrant and palbociclib (arm A), gedatolisib in combination with fulvestrant (arm B), or fulvestrant alone (arm C).[3] Participants received treatment until disease progression or unacceptable toxicity.[3]

Clinical trials

[edit]

A number of early phase clinical trials of gedatolisib for treatment of endometrial cancer, colorectal cancer, acute myeloid leukemia have been conducted.[10][11][12]

Clinical trials are focused on breast cancer.[13][14][15][16]

Society and culture

[edit]
[edit]

Gedatolisib was approved for medical use in the United States in July 2026.[17]

Names

[edit]

Gedatolisib is the international nonproprietary name.[18]

Gedatolisib is sold under the brand name Revtorpyk.[1]

References

[edit]
  1. 1 2 3 4 5 6 7 8 9 "Highlights of prescribing information - REVTORPYK (gedatolisib) for Injection, for intravenous infusion" (PDF). celcuity.com.
  2. ↑ Dehnhardt CM, Venkatesan AM, Chen Z, Delos-Santos E, Ayral-Kaloustian S, Brooijmans N, et al. (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.
  3. 1 2 3 4 5 "FDA approves gedatolisib with fulvestrant, with or without palbociclib, for HR-positive, HER2-negative locally advanced or metastatic breast cancer". U.S. Food and Drug Administration (FDA). 14 July 2026. Retrieved 20 July 2026. Public Domain This article incorporates text from this source, which is in the public domain.
  4. ↑ 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. Bibcode:2017PNAS..11411818S. doi:10.1073/pnas.1716173114. PMC 5692607. PMID 29078414.
  5. ↑ 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.
  6. ↑ 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. PMC 6612215. PMID 31277692.
  7. ↑ 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. PMC 9297732. PMID 34127844. S2CID 235437841.
  8. ↑ 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.
  9. ↑ Anderson EJ, Mollon LE, Dean JL, Warholak TL, Aizer A, Platt EA, et al. (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.
  10. ↑ 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
  11. ↑ 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
  12. ↑ 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
  13. ↑ Clinical trial number NCT03698383 for "Phase II Study of Herzuma® Plus Gedatolisib in Patients With HER-2 Positive Metastatic Breast Cancer" at ClinicalTrials.gov
  14. ↑ Clinical trial number NCT03911973 for "Gedatolisib Plus Talazoparib in Advanced Triple Negative or BRCA1/2 Positive, HER2 Negative Breast Cancers" at ClinicalTrials.gov
  15. ↑ 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
  16. ↑ 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
  17. ↑ "Celcuity Announces FDA Approval of Revtorpyk (gedatolisib) for the Treatment of HR+/HER2-, PIK3CA Wild-Type Locally Advanced or Metastatic Breast Cancer" (Press release). Celcuity. 14 July 2026. Retrieved 20 July 2026 – via GlobeNewswire.
  18. ↑ World Health Organization (2015). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 73". WHO Drug Information. 29 (1). hdl:10665/331088.
[edit]
  • Clinical trial number NCT05501886 for "Gedatolisib Plus Fulvestrant With or Without Palbociclib vs Standard-of-Care for the Treatment of Patients With Advanced or Metastatic HR+/HER2- Breast Cancer (VIKTORIA-1) (VIKTORIA-1)" at ClinicalTrials.gov
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