RESUMO
A coprime array of M + N - 1 elements is designed, using product processing (PP), to yield the same beam width as that of a full array of MN elements using conventional beamforming (CBF), while at the same time suppressing the grating lobes. The array gain (AG) for isotropic noise using conventional PP is slightly less than that obtained using CBF, namely, 10log(M + N - 1). It is shown that using the coherent product processing, the coprime array yields an AG equal to that of the full array of MN elements, 10log(MN). The superior gain is often referred to as supergain.
RESUMO
Protein-protein interactions (PPIs) stabilization with molecular glues plays a crucial role in drug discovery, albeit with significant challenges. In this study, we propose a dual-site approach, targeting the PPI region and its dynamic surroundings. We conduct molecular dynamics simulations to identify critical sites on the PPI that stabilize the cyclin-dependent kinase 12 - DNA damage-binding protein 1 (CDK12-DDB1) complex, resulting in further cyclin K degradation. This exploration leads to the creation of LL-K12-18, a dual-site molecular glue, which enhances the glue properties to augment degradation kinetics and efficiency. Notably, LL-K12-18 demonstrates strong inhibition of gene transcription and anti-proliferative effects in tumor cells, showing significant potency improvements in MDA-MB-231 (88-fold) and MDA-MB-468 cells (307-fold) when compared to its precursor compound SR-4835. These findings underscore the potential of dual-site approaches in disrupting CDK12 function and offer a structural insight-based framework for the design of cyclin K molecular glues.