Lead structure optimization of compounds identified to induce differentiation in solid tumors

Purpose:

A high compound pharmacological potency, which is determined by the drug affinity as well as efficacy, is an important requirement for a favourable drug candidate development towards its clinical application. Especially, hit candidates identified by phenotype-based screenings require an extensive medicinal chemical optimization since compound-target interactions are mostly unknown preventing more specific molecular modifications. Thus, performing phenotypic screening to target rarely investigated pathophysiological mechanisms like activating differentiation programs to overcome tumor specific differentiation blocks in solid tumors requires early derivatisation of identified hits for successful drug development.

Methods:

Based on a novel cell-based phenotypic high-throughput screening system we identified two compounds which induce differentiation in triple-negative breast cancer and non-small cell lung cancer, respectively. To generate compounds with an increased pharmacological potency, selected hits were chosen for distinct chemical modifications and investigated for their differentiation inducing capacity in MDA-MB-231 and A549 cells via dose-response analysis.

Results:

Among the derivates tested we detected one compound for each tumor entity with significantly increased pharmacological potency compared to the hits originally identified by the primary screening. In contrast, the remaining derivates showed no or an only reduced effect.

Conclusions:

We have successfully optimized the differentiating potency for two novel substance classes in MDA-MB-231 and A549 cancer cell lines. Validation in secondary tests and further lead structure optimization will be performed to further develop the selected compounds towards a clinical application.