A novel methodology for the coupling of alkenes with aldehyde-or ketone-derived Cbzhydrazones to form a new CC bond through a radical process is described. The sequence comprises an initial in situ generation of an iron hydride followed by a hydrogen atom transfer to an alkene, a coupling with a hydrazone and a final reduction of the nitrogencentered radical. Hydrogenation of the obtained hydrazines renders amines, including valuable tert-alkyl amines.

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We report a series of small molecule proteolysis-targeting chimeras (PROTACs) that target the protein kinase p38α for degradation. These PROTACs are based on a ligand of the VHL E3 ubiquitin ligase, which is linked to an ATP competitive inhibitor of p38α. We provide evidence that these compounds can induce the specific degradation of p38α, but not p38β and other related kinases, at nanomolar concentrations in several mammalian cell lines. We also show that the p38α-specific PROTACs are soluble in aqueous solutions and therefore suitable for their administration to mice. Systemic administration of the PROTACs induces p38α degradation only in the liver, probably due to the PROTAC becoming inactivated in that organ, but upon local administration the PROTACs induce p38α degradation in mammary tumors. Our compounds provide an alternative to traditional chemical inhibitors for targeting p38α signaling in cultured cells and in vivo.

In the last four decades, treatment of oestrogen receptor positive (ER+) breast cancer (BCa), has focused on targeting the estrogenic receptor signaling pathway. This signaling function is pivotal to sustain cell proliferation. Tamoxifen, a competitor inhibitor of oestrogen has played a major role in therapeutics. However, primary and acquired resistance to hormone blockade occurred in a large subset of these cancers, and new approaches were urgently needed. Aromatase inhibitors and receptor degraders were approved and alternatively used. Yet, resistance appears in the metastatic setting. Here we report the design and synthesis of a series of proteolysis targeting chimeras (PROTACs) that induce the degradation of estrogen receptor alpha in breast cancer MCF-7 (ER+) cells at nanomolar concentration. Using a warhead based on 4-hydroxitamoxifen, bifunctional degraders recruiting either cereblon or the Von Hippel Lindau E3 ligases were synthesized. Our efforts resulted in the discovery of TAM-VHL-1, a potent ERα degrader (DC50: 4.5 nM) that we envisage as a useful tool for biology study and a platform for potential therapeutics.