Discovery of XL01126: A Potent, Fast, Cooperative, Selective, Orally Bioavailable, and Blood-Brain Barrier Penetrant PROTAC Degrader of Leucine-Rich Repeat Kinase 2.

Leucine-rich repeat kinase 2 (LRRK2) is one of the most promising targets for Parkinson's disease. LRRK2-targeting strategies have primarily focused on type 1 kinase inhibitors, which, however, have limitations as the inhibited protein can interfere with natural mechanisms, which could lead to undesirable side effects. Herein, we report the development of LRRK2 proteolysis targeting chimeras (PROTACs), culminating in the discovery of degrader XL01126, as an alternative LRRK2-targeting strategy.

The Lisbon Supramolecular Green Story: Mechanochemistry towards New Forms of Pharmaceuticals.

This short review presents and highlights the work performed by the Lisbon Group on the mechanochemical synthesis of active pharmaceutical ingredients (APIs) multicomponent compounds. Here, we show some of our most relevant contributions on the synthesis of supramolecular derivatives of well-known commercial used drugs and the corresponding improvement on their physicochemical properties. The study reflects, not only our pursuit of using crystal engineering principles for the search of supramolecular entities, but also our aim to correlate them with the desired properties.

Targeting leucine-rich repeat kinase 2 (LRRK2) for the treatment of Parkinson's disease.

Leucine-rich repeat kinase 2 (LRRK2) is a serine-threonine kinase involved in multiple cellular processes and signaling pathways. mutations are associated with autosomal-inherited Parkinson's disease (PD), and evidence suggests that LRRK2 pathogenic variants generally increase kinase activity. Therefore, inhibition of LRRK2 kinase function is a promising therapeutic strategy for PD treatment.

Enhanced cytotoxicity of prenylated chalcone against tumour cells via disruption of the p53-MDM2 interaction.

Aim: Chalcones are naturally occurring compounds with recognized anticancer activity. It was recently shown that the O-prenyl derivative (2) of 2'-hydroxy-3,4,4',5,6'-pentamethoxychalcone (1) had a remarkably increased cytotoxicity against human tumour cells compared to its precursor. With this study, we aimed to investigate the molecular mechanism underlying the improved tumour cytotoxicity of prenylchalcone 2.

New forms of old drugs: improving without changing.

Objectives: In a short approach, we want to present the improvements that have recently been done in the world of new solid forms of known active pharmaceutical ingredients (APIs). The different strategies will be addressed, and successful examples will be given.

Key Findings: This overview presents a possible step to overcome the 10-15 years of hard work involved in launching a new drug in the market: the use of new forms of well-known APIs, and improve their efficiency by enhancing their bioavailability and pharmacokinetics.