Structural perspectives of the CYP3A family and their small molecule modulators in drug metabolism

Cytochrome P450(CYP)enzymes function to catalyze a wide range of reactions,many of which are critically important for drug response.Members of the human cytochrome P4503A(CYP3A)family are particularly important in drug clearance,and they collectively metabolize more than half of all currently prescribed medications.The ability of these enzymes to bind a large and structurally diverse set of compounds increases the chances of their modulating or facilitating drug metabolism in unfavorable ways.Emerging evidence suggests that individual enzymes in the CYP3A family play discrete and important roles in catalysis and disease progression.Here we review the similarities and differences among CYP3A enzymes with regard to substrate recognition,metabolism,modulation by small molecules,and biological consequence,highlighting some of those with clinical significance.We also present structural perspectives to further characterize the basis of these comparisons.

Small molecules targeting the innate immune cGAS-STING-TBK1 signaling pathway

Multiple cancer immunotherapies including chimeric antigen receptor T cell and immune checkpoint inhibitors(ICIs)have been successfully developed to treat various cancers by motivating the adaptive anti-tumor immunity.Particularly,the checkpoint blockade approach has achieved great clinic success as evidenced by several U.S.Food and Drug Administration(FDA)-approved antiprogrammed death receptor 1/ligand 1 or anti-cytotoxic T lymphocyte associated protein 4 antibodies.However,the majority of cancers have low clinical response rates to these ICIs due to poor tumor immunogenicity.Indeed,the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes-TANK-binding kinase 1(cGAS-STING-TBK1)axis is now appreciated as the major signaling pathway in innate immune response across different species.Aberrant signaling of this pathway has been closely linked to multiple diseases,including auto-inflammation,virus infection and cancers.In this perspective,we provide an updated review on the latest progress on the development of small molecule modulators targeting the cGAS-STING-TBK1 signaling pathway and their preclinical and clinical use as a new immune stimulatory therapy.Meanwhile,highlights on the clinical candidates,limitations and challenges,as well as future directions in this field are also discussed.Further,small molecule inhibitors targeting this signaling axis and their potential therapeutic use for various indications are discussed as well.