Identification of novel mycocompounds as inhibitors of PI3K/AKT/mTOR pathway against RCC

Abstract

PI3K/AKT/mTOR pathway is one of the frequently disrupted signaling pathways in renal cell carcinoma (RCC) that plays a significant role in tumor formation, disease progression and therapeutic resistance. Therefore, novel natural molecules targeting the critical proteins of this pathway will provide the best alternative to existing drugs, which are toxic and develops resistance. Recent studies have recognized the anti-cancer therapeutic potential of mycocompounds. The current study is focused on screening various mycocompounds from Astraeus hygrometricus against key cancer signaling proteins phosphoinositide 3‐kinase (PI3K), protein kinase B, PKB (AKT1) and mammalian target of rapamycin (mTOR). We also studied in-silico cancer cells cytotoxicity and ADMET (absorption, distribution, metabolism, excretion and toxicity) profiles to elucidate the molecular mechanism against RCC and also to uncover the pharmacokinetic profile of these compounds. Astrakurkurone and Ergosta-4,6, 8-(14) 22-tetraene-3-one were the two most efficacious compounds with highest interaction scores and bonding. These compounds were both active against RCC4 and VMRC-RCZ cell lines of RCC. The ADME profiles of both were satisfactory based on druglikeness and bioavailability score criteria. Thus, this proposed study identified astrakurkurone and ergosta-4,6, 8-(14) 22-tetraene-3-one as potential anticancer drug candidates, and provides comparative structural insight into their binding to the 3 protein kinases.

Keywords:

• Renal cell carcinoma
• A. hygrometricus
• astrakurkurone
• molecular docking
• PI3K/AKT/mTOR pathway
• anti-cancer sensitivity prediction

Acknowledgement

The authors are thankful to the Indian Council of Medical Research, New Delhi, Govt. of India for their financial assistance in the form of Senior Research Fellowship to RPY Ref. 2020-8020/GEN-BMS.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The data that support the findings of this study are available from the corresponding author, [Das M.], upon reasonable request.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.