Marcos Pires

Androgen receptor (AR)-dependent transcription is a major driver of prostate tumor cell proliferation. Consequently, it is the target of several antitumor chemotherapeutic agents, including the AR antagonist MDV3100/enzalutamide. Recent studies have shown that a single AR mutation (F876L) converts MDV3100 action from an antagonist to an agonist. Here we describe the generation of a novel class of selective androgen receptor degraders (SARDs) to address this resistance mechanism. Molecules containing hydrophobic degrons linked to small-molecule AR ligands induce AR degradation, reduce expression of AR target genes and inhibit proliferation in androgen-dependent prostate cancer cell lines. These results suggest that selective AR degradation may be an effective therapeutic prostate tumor strategy in the context of AR mutations that confer resistance to second-generation AR antagonists.

Making the problem go away: Most prostate tumor growth is driven by the action of the androgen receptor (AR). Resistance to current chemotherapies for prostate cancer can occur when the androgen receptor is either overexpressed or mutated. Coupling of an AR agonist to an adamantyl “hydrophobic tag” resulted in a molecule that induces AR degradation, even in drug-resistant prostate tumor cells.

A UV-induced 1,3-dipolar nucleophilic addition of tetrazoles to thiols is described. Under UV irradiation the reaction proceeds rapidly at room temperature, with high yields, without a catalyst, and in both polar protic and aprotic solvents, including water. This UV-induced tetrazole-thiol reaction was successfully applied for the synthesis of small molecules, protein modification, and rapid and facile polymer–polymer conjugation. The reaction has also been demonstrated for the formation of micropatterns by site-selective surface functionalization. Superhydrophobic–hydrophilic micropatterns were successfully created by sequential modifications of a tetrazole-modified porous polymer surface with hydrophobic and hydrophilic thiols. A biotin-functionalized surface could be fabricated in aqueous solutions under long-wavelength UV irradiation.

Without catalyst: A UV-induced tetrazole-thiol reaction is reported. This reaction proceeds rapidly at ambient temperature under UV light in different solvents including water with high yield and without a catalyst. The reaction has been demonstrated for small-molecule and polymer–polymer conjugation, as well as for rapid site-selective surface functionalization and patterning.

Protease-triggered CO-releasing molecules (CORMs) were developed. The viability of the approach was demonstrated through the synthesis of compounds consisting of an η⁴-oxydiene–Fe(CO)₃ moiety connected to a penicillin G amidase (PGA)-cleavable unit through a self-immolative linker. The rate of PGA-induced hydrolysis was investigated by HPLC analysis and the subsequent CO release was quantitatively assessed through headspace gas chromatography. In an in vitro assay with human endothelial cells, typical biological effects of CO, that is, inhibition of the inflammatory response and the induction of heme oxygenase-1 expression, were observed only upon co-administration of the CORM and PGA. This work forms a promising basis for the future development of protease-specific CORMs for potential medicinal applications.

Please release me, let me CO: As an important step towards the development of protease-triggered CO-releasing molecules (CORMs), oxydiene–Fe(CO)₃ complexes bearing a penicillin G amidase (PGA)-cleavable side chain connected to the organometallic unit through a self-immolative linker were designed and synthesized. PGA-induced CO release was confirmed by headspace GC and by inhibition of VCAM-1 expression in a cell-based assay.

Disulfide-rich peptides containing three or more disulfide bonds are promising therapeutic and diagnostic agents, but their preparation is often limited by the tedious and low-yielding folding process. We found that a single cystine-to-diaminodiacid replacement could significantly increase the folding efficiency of disulfide-rich peptides and thus improve their production yields. The practicality of this strategy was demonstrated by the synthesis and folding of derivatives of the μ-conotoxin SIIIA, the preclinical hormone hepcidin, and the trypsin inhibitor EETI-II. NMR and X-ray crystallography studies confirmed that these derivatives of disulfide-rich peptide retained the correct three-dimensional conformations. Moreover, the cystine-to-diaminodiacid replacement enabled structural tuning, thereby leading to an EETI-II derivative with higher bioactivity than the native peptide.

Bridging the gap: A single cystine-to-diaminodiacid replacement can enable the efficient production and optimization of disulfide-rich peptides. The practicability and advantages of this method were demonstrated through studies with the μ-conotoxin SIIIA, the hormone hepcidin, and the trypsin inhibitor EETI-II.

News from the antibiotics pipeline: The discovery of a depsipeptide-type lipid II binder, isolated from a previously unknown bacterium, raises hopes in the battle against multiresistant staphylococci.