Computationally prioritized drugs inhibit SARS-CoV-2 infection and syncytia formation.

The pharmacological arsenal against the COVID-19 pandemic is largely based on generic anti-inflammatory strategies or poorly scalable solutions. Moreover, as the ongoing vaccination campaign is rolling slower than wished, affordable and effective therapeutics are needed. To this end, there is increasing attention toward computational methods for drug repositioning and de novo drug design. Here, multiple data-driven computational approaches are systematically integrated to perform a virtual screening and prioritize candidate drugs for the treatment of COVID-19. From the list of prioritized drugs, a subset of representative candidates to test in human cells is selected. Two compounds, 7-hydroxystaurosporine and bafetinib, show synergistic antiviral effects in vitro and strongly inhibit viral-induced syncytia formation. Moreover, since existing drug repositioning methods provide limited usable information for de novo drug design, the relevant chemical substructures of the identified drugs are extracted to provide a chemical vocabulary that may help to design new effective drugs.

Bafetinib Suppresses the Transcription of PD-L1 Through c-Myc in Lung Cancer.

Given the limitations of the existing antibody-based therapies, including immune-related adverse events, poor response rates, and intravenous route of dosing, small molecules inhibitors targeting PD-L1 are highly desirable. By cell-based screening, we found that tyrosine kinase inhibitor Bafetinib dramatically suppresses PD-L1 protein expression in a dose-dependent manner. In parallel, cell membrane PD-L1 is also reduced by Bafetinib. We confirm that Bafetinib doesn't affect the protein half-life of PD-L1 but significantly inhibits the transcription of PD-L1. Among the transcription factors that regulate PD-L1 expression, c-Myc is downregulated by Bafetinib. Bafetinib caused PD-L1 inhibition is abolished when c-Myc is knocked-down. Further, we identified that Bafetinib reduced c-Myc expression because of transcription inhibition. By using the CT26 tumor model, we further confirm that Bafetinib suppressed PD-L1 expression in vivo. In conclusion, our study shows that Bafetinib inhibits the transcription of PD-L1 through transcription factor c-Myc, suggesting that Bafetinib might be a small molecule drug targeting PD-L1.

Bafetinib inhibits functional responses of human eosinophils in vitro.

Eosinophils play a prominent role in the process of allergic inflammation. Non-receptor associated Lyn tyrosine kinases generate key initial signals in eosinophils. Bafetinib, a specific Abl/Lyn tyrosine kinase inhibitor has shown a potent antiproliferative activity in leukemic cells, but its effects on eosinophils have not been reported. Therefore, we studied the effects of bafetinib on functional and mechanistic responses of isolated human eosinophils. Bafetinib was more potent than non-specific tyrosin kinase comparators genistein and tyrphostin inhibiting superoxide anion triggered by N-formyl-Met-Leu-Phe (fMLF; 100 nM) (-log IC50=7.25 ± 0.04 M; 6.1 ± 0.04 M; and 6.55 ± 0.03 M, respectively). Bafetinib, genistein and tyrphostin did not modify the [Ca(2+)]i responses to fMLF. Bafetinib inhibited the release of EPO induced by fMLF with higher potency than genistein and tyrphostin (-log IC50=7.24 ± 0.09 M; 5.36 ± 0.28 M; and 5.37 ± 0.19 M, respectively), and nearly suppressed LTC4, ECP and chemotaxis. Bafetinib, genistein and tyrphostin did not change constitutive apoptosis. However bafetinib inhibited the ability of granulocyte-monocyte colony-stimulating factor to prevent apoptosis. The activation of Lyn tyrosine kinase, p-ERK1/2 and p-38 induced by fMLF was suppressed by bafetinib and attenuated by genistein and tyrphostin. In conclusion, bafetinib inhibits oxidative burst and generation of inflammatory mediators, and reverses the eosinophil survival. Therefore, future anti-allergic therapies based on bafetinib, could help to suppress excessive inflammatory response of eosinophils at inflammatory sites.