Design, Synthesis and Phenotypic Profiling of Simplified Gedatolisib Analogues

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Oncology

Background:

• Targeted antitumour therapy offers new cancer treatment strategies.
• Phosphatidylinositol-3 kinase (PI3K) is a validated target in cancer therapy.
• Gedatolisib is an established PI3K inhibitor used in cancer treatment.

Purpose of the Study:

• To design and synthesise simplified analogues of gedatolisib.
• To evaluate the cytotoxic activity of these novel compounds against various tumour cell lines.
• To identify a lead compound with improved properties for potential cancer therapy.

Main Methods:

• Synthesis of gedatolisib analogues (5a-f).
• Phenotypic evaluation of cytotoxic activity in solid and nonadherent tumour cell lines.
• Assessment of physicochemical properties including aqueous solubility and partition coefficient.
• Metabolic stability assessment using rat liver microsomes.
• Flow cytometry analysis to confirm PI3K pathway modulation.

Main Results:

• Compound 5f (LASSBio-2252) emerged as the most promising analogue.
• 5f exhibited good aqueous solubility (42.38 μM at pH 7.4) and a favourable partition coefficient (cLogP = 2.96).
• Significant cytotoxic activity was observed against human leukemia cell lines (CCRF-CEM, K562, MOLT-4).
• 5f demonstrated excellent metabolic stability (t1/2 = 462 min) and low clearance (Clapp = 0.058 mL/min/g).
• Flow cytometry confirmed that 5f modulates the PI3K pathway, similar to gedatolisib.

Conclusions:

• Simplified gedatolisib analogues were successfully synthesised.
• Compound 5f (LASSBio-2252) represents a promising candidate for further development in cancer therapy.
• 5f displays a favourable profile of cytotoxic activity, solubility, metabolic stability, and PI3K pathway inhibition.