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 The mammalian target of sirolimus, rapamycin (mTOR), also referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the ''MT ...

. 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.

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. 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.

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 Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. Cell proliferation re ...

, 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.

Clinical trials

A number of early phase clinical trials of gedatolisib for treatment of

endometrial cancer Endometrial cancer is a cancer that arises from the endometrium (the lining of the uterus or womb). It is the result of the abnormal growth of cells that have the ability to invade or spread to other parts of the body. The first sign is most o ...

colorectal cancer Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel m ...

, acute myeloid leukemia have been conducted. Current clinical trials are focused on

breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a re ...

References

{{USGovernment, url=https://www.sec.gov/Archives/edgar/data/1603454/000165495421003990/celc_ex993.htm Experimental cancer drugs Pfizer brands 4-Morpholinyl compunds Triazines Ureas Benzamides Phosphoinositide 3-kinase inhibitors