Topical BET PROTACs for locally restricted protein degradation in the lung

Abstract

Proteolysis targeting chimeras (PROTACs) have been studied extensively to optimize their oral bioavailability. Based on Lipinski’s and Veber’s rules, molecular weight, logP, logD, the number of hydrogen bond donors and acceptors, the polar surface area and the number of rotatable bonds play a critical role for the oral bioavailability of any given PROTAC. Multiple analyses of the published PROTAC chemical space show that the overall guidelines for obtaining orally available PROTACs are broadly in line with those of the bRo5 space established for oral drugs. In contrast to the significant knowledge that has been generated for the design of oral PROTACs, there is little expertise regarding inhaled and generally topically administered PROTACs. In this work we (1) introduce parameters influencing the inhaled route of administration of PROTACs and (2) describe the first examples of inhaled bromodomain and extra terminal domain (BET) PROTACs which were designed for inhaled delivery and characterized in vitro and in vivo.