Structure-based optimization leads to the discovery of NSC765844, a highly potent, less toxic and orally efficacious...

Area of Science:

• Oncology
• Medicinal Chemistry
• Pharmacology

Background:

• The phosphoinositide 3-kinase (PI3K) pathway is frequently dysregulated in human cancers, making PI3K inhibition a key therapeutic strategy.
• Dual inhibition of PI3K and mTOR offers a promising approach to overcome resistance and enhance efficacy in cancer treatment.

Purpose of the Study:

• To design and synthesize novel benzylamine substituted arylsulfonamides as dual PI3K/mTOR inhibitors.
• To evaluate the in vitro and in vivo anticancer potential of the identified lead compound, 13b (NSC765844).

Main Methods:

• Focused library design and virtual screening were employed to identify potential dual PI3K/mTOR inhibitors.
• Enzyme inhibition assays determined the potency of synthesized compounds against PI3K isoforms and mTOR.
• In vitro cytotoxic screening against a panel of human tumor cell lines and in vivo xenograft models were used for efficacy evaluation.

Main Results:

• Compound 13b exhibited potent inhibition of PI3Kα, β, γ, δ, and mTOR with nanomolar IC50 values.
• 13b demonstrated broad-spectrum antitumor activity in vitro, with a mean GI50 of 18.6 nM against approximately 60 human tumor cell lines.
• In vivo studies showed significant inhibition of tumor growth in A549 non-small-cell lung carcinoma and BEL7404 human hepatocellular carcinoma xenograft models.

Conclusions:

• Compound 13b is a potent dual PI3K/mTOR inhibitor with significant in vitro and in vivo anticancer activity.
• Favorable physicochemical and pharmacokinetic properties support its further development.
• 13b represents a promising drug candidate for preclinical investigation in cancer therapy.