Design of PI3K-mTOR Dual Inhibitors for Ovarian Cancer: Are we on the Right Track?

Abstract

Ovarian cancer is one of the most familiar kinds of gynecological cancer seen in women. Though it is not as familiar as breast cancer, the survival rate for ovarian cancer is very low when compared with breast cancer. Even after being one among the familiar types, to date, there are no proper treatments available for ovarian cancer. All the treatments that are present currently show a high rate of recurrence after the treatment. Therefore, treating this silent killer from the roots is the need of the hour. PI3K/AKT/m-TOR pathway is one of the pathways that get altered during ovarian cancer. Studies are already going on for the inhibition of PI3K and mTOR separately. Efforts have been made to inhibit either PI3K or mTOR separately earlier. However, due to its side effects and resistance to the treatments available, current studies are based on the inhibition of PI3K and mTOR together. Inhibition of PI3K and mTOR simultaneously reduces the chances of negative feedback, thus decreasing the toxicity. This review contains the evolution of PI3K and mTOR drugs that are approved by the FDA and are in the trials for different cancer types, including ovarian cancer. In this article, how a molecular targeted therapy can be made successful and free from toxicity for treating ovarian cancer is discussed. Therefore, this review paves the way for finding an effective scaffold rather than the clinical part. The scaffold thus selected can be further modified and synthesized in the future as dual PI3K/mTOR inhibitors specifically for OC.

Keywords: Ovarian cancer; PI3K/AKT/mTOR pathway; breast cancer; dual inhibitors; fallopian tube.; triazine.

Fig. (1)

(a) Pie chart showing the mortality rate of ovarian cancer. (b) Schematic representation of pathways of ovarian cancer.

Fig. (2)

PI3K inhibitor compounds 1-12.

Fig. (3)

First-generation mTOR inhibitors.

Fig. (4)

(a) Pyrido[2,3-d]pyrimidine derivatives. (b) Pyrazolo[3,4-d]pyrimidines derivatives. (c) 4-Aminopyrazolo[3,4-d]pyrimidines derivatives. (d) Thieno[3,2-d]pyrimidines derivatives. (e) Benzo [h]1,6-naphthyridin-2-ones derivatives. Second-generation mTOR inhibitors mentioned in (a-e).

Fig. (5)

(a) First dual PI3K/mTOR. (b) Dual PI3K/mTOR inhibitors. (c) Sulphonamide dual PI3K/mTOR inhibitors. (d) Dual PI3K/mTOR inhibitor compounds 51 and 52. (e) Dual PI3K/mTOR inhibitor compounds 53-56. Dual PI3K/mTOR inhibitors with different scaffolds mentioned in (a-e).