Enteroviruses (EVs) are among the most frequent infectious agents in humans worldwide and represent the leading cause of upper respiratory tract infections. No drugs for the treatment of EV infections are currently available. Recent studies have also linked EV infection with pulmonary exacerbations, especially in cystic fibrosis (CF) patients, and the importance of this link is probably underestimated. The aim of this work was to develop a new class of multitarget agents active both as broad-spectrum antivirals and as correctors of the F508del-cystic fibrosis transmembrane conductance regulator (CFTR) folding defect responsible for >90% of CF cases. We report herein the discovery of the first small molecules able to simultaneously act as correctors of the F508del-CFTR folding defect and as broad-spectrum antivirals against a panel of EVs representative of all major species.

To gether with estrogen receptors ERa and ERb,t he Gproteincoupled estrogen receptor (GPER) mediates important pathophysiological signaling pathways induced by estrogens andi s currently regardeda sapromising target for ER-negative (ERÀ) and triple-negative( TN) breast cancer.O nly af ew selective GPER modulators have been reported to date, and their use in cancer cell lines has often led to contradictory results. Herein we report the application of virtuals creening and cell-based studies for the identification of new chemical scaffoldsw ith as pecific antiproliferative effect against GPER-expressing breast cancer cell lines. Out of the four different scaffolds identified, 8-chloro-4-(4-chlorophenyl)pyrrolo[1,2-a]quinoxaline 14 c was found to be the most promising compound able to induce:1 )antiproliferativea ctivity in GPER-expressing cell lines (MCF7 and SKBR3), similarly to G15;2 )noe ffect on cells that do not expressG PER (HEK293);3 )a decrease in cyclin D1 expression;a nd 4) as ustained induction of cell-cycle negative regulators p53 and p21.Breast cancer is the most common cancer diagnosis in women and the mostc ommon cause of cancer-related mortality among females worldwide, with current predictions and statistics suggesting that both incidence and mortality rates are on the rise. [1] Hormone receptor (HR) positive breast cancer( HR +) is the most common form of breast cancer( 85 %o fa ll breast cancers)a nd has ag ood prognosis thanks to endocrine therapy (e.g.,t amoxifen) and administration of aromatase inhibitors (e.g.,l etrozole). HRÀ human epidermal growth factor receptor 2p ositive (HER2 +), andt riple-negative (TN) breastc ancers (HER2À,E R aÀ,E R bÀ)h ave al ower incidence, but whereas HER2 + tumors can be treated with targeted therapies (e.g., trastuzumab),T Nt umorsh ave the worst prognosis, ag reater chance of recurrence, andnot argeted treatments. [2] Estrogen hormones playakey role not only in the regulation of multiple physiological processes, but also in promoting the proliferation of the neoplastic breast epithelium by acting on soluble nuclear estrogen receptors (ERa and ERb). [3] While tamoxifeni sawidely used selectivee strogen receptorm odulator (SERM) and displays anti-estrogenic (and therefore anticancer) effects in the breast, it also has pro-estrogenic activity in the endometrium, enhancing the risk of developing endometrial cancer. However,t he therapeutic benefito ft amoxifen in the treatment of breast cancer has been considered to outweigh the risk of developinge ndometrial canceri np remenopausal women. [4] These side effects seem to be due to the active metabolite of tamoxifen (4-hydroxytamoxifen, 4-OHT), which acts as an agonistf or at hird estrogenr eceptor involved in the rapid non-genomic response to estrogens:t he Gprotein-coupled estrogen receptor (GPER or GPR30). [5] GPER is now emerging as an ew potentialt arget for the treatment of severalh uman diseases such as cardiovascular,r enal, and proteinuria diseases and malignancy. [6] In the field of anticancer drug disco...

No abstract

Cystic fibrosis (CF) is a multi-organ protein misfolding disease caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR). In addition to respiratory impairment due to mucus accumulation, viruses, bacteria and their co-infections are recognized triggers of acute pulmonary exacerbations, accelerating disease progression, and increasing hospitalization and mortality rate. Treatment complexity increases with the age of patients, as do the number and severity of side effects, drug-drug interactions and costs. Simplifying the therapeutic regimen represents therefore one of the key priorities of CF treatment. We have recently reported the discovery of multitarget compounds able to "kill two birds with one stone" by targeting F508del-CFTR and PI4KIIIβ and thus acting simultaneously as mild correctors and broad-spectrum picornavirus inhibitors. Starting from the previously identified multitarget hits, we report herein the synthesis and biological profiling of new bithiazole derivatives to elucidate the structural requirements to improve F508del-CFTR correction and antiviral potencies. The most promising compound 23a inhibited PI4KIIIβ and selected picornaviruses (EV71, CVB3, hRV02), showed good F508del-CFTR correction potency, additivity and possible synergy with lumacaftor (VX809) at low micromolar concentration. In addition, it was well tolerated in vivo by C57BL/6 mice with no sign of acute toxicity and histological alterations in key biodistribution organs.

Herein we report the development of a new versatile chemical tool for the rapid identification of LRRK2-targeting probes as potential anti-Parkinson's agents.