PROTAC-mediated degradation of Bruton's tyrosine kinase is inhibited by covalent binding

The impact of covalent binding on PROTAC-Mediated degradation of BTK was investigated through the preparation of both covalent binding and reversible binding PROTACs derived from the covalent BTK inhibitor ibrutinib. It was determined that a covalent binding PROTAC inhibited BTK degradation despite evidence of target engagement, while BTK degradation was observed with a reversible binding PROTAC. These observations were consistently found when PROTACs that were able to recruit either IAP or cereblon E3 ligases were employed. Proteomics analysis determined that the use of a covalently bound PROTAC did not result in the degradation of covalently bound targets, while degradation was observed for some reversibly bound targets. This observation highlights the importance of catalysis for successful PROTAC-Mediated degradation and highlights a potential caveat for the use of covalent target binders in PROTAC design

Selectively targeting the kinome-conserved lysine of PI3K (delta) as a general approach to covalent kinase inhibition

Selective covalent inhibition of kinases by targeting poorly conserved cysteines has proven highly fruitful to date in the development of chemical probes and approved drugs. However, this approach is limited to ~200 kinases possessing such a cysteine near the ATP-binding pocket. Herein, we report a novel approach to achieve selective, irreversible kinase inhibition, by targeting the conserved catalytic lysine residue. We have illustrated our approach by developing selective, covalent PI3Kδ inhibitors that exhibit nanomolar potency in cellular assays, and a duration of action >48 h in CD4+ T cells. Despite conservation of the lysine residue throughout the kinome, the lead compound shows high levels of selectivity over a selection of lipid and protein kinases in biochemical assays, as well as covalent binding to very few off-target proteins in live-cell proteomic studies. We anticipate this approach could offer an alternative general strategy, to targeting non-conserved cysteines, for the development of selective covalent kinase inhibitors

Mother-male bond, but not paternity, influences male-infant affiliation in wild crested macaques

In promiscuous primates, interactions between adult males and infants have rarely been investigated. However, recent evidence suggests that male affiliation towards infants has an influence on several aspects of the infants’ life. Furthermore, affiliations may be associated with male reproductive strategy. In this study, we examined which social factors influenced male-infant affiliation initiated by either male or infant, in wild crested macaques (Macaca nigra). We combined behavioral data and genetic paternity analysis from 30 infants living in three wild groups in Tangkoko Reserve, Indonesia. Our results indicate that adult males and infants do not interact at random, but rather form preferential associations. The social factors with the highest influence on infant-initiated interactions were male rank and male association with the infant’s mother. While infants initiated affiliations with males more often in the absence of their mothers, adult males initiated more affiliations with infants when their mothers were present. Furthermore, males initiated affiliations more often when they were in the same group at the time the infant was conceived, when they held a high dominance rank or when they had a close relationship with the mother. Interestingly, paternity did not affect male-infant affiliation despite being highly skewed in this species. Overall, our results suggest that adult males potentially associate with an infant to secure future mating with the mother. Infants are more likely to associate with a male to receive better support, suggesting a strategy to increase the chance of infant survival in a primate society with high infant mortality