Biologic-like In Vivo Efficacy with Small Molecule Inhibitors of TNFα Identified Using Scaffold Hopping and Structure-Based Drug Design Approaches

Abstract

Scaffold hopping and structure-based drug design were employed to identify substituted 4-aminoquinolines and 4-aminonaphthyridines as potent, small molecule inhibitors of tumor necrosis factor alpha (TNFα). Structure–activity relationships in both the quinoline and naphthyridine series leading to the identification of compound 42 with excellent potency and pharmacokinetic profile are discussed. X-ray co-crystal structure analysis and ultracentrifugation experiments clearly demonstrate that these inhibitors distort the TNFα trimer upon binding, leading to aberrant signaling when the trimer binds to TNF receptor 1 (TNFR1). Pharmacokinetic–pharmacodynamic activity of compound 42 in a TNF-induced IL-6 mouse model and in vivo activity in a collagen antibody-induced arthritis model, where it showed biologic-like in vivo efficacy, will be discussed.

In Silico Identification and Evaluation of Natural Products as Potential Tumor Necrosis Factor Function Inhibitors Using Advanced Enalos Asclepios KNIME Nodes

“…O’Connell et al [ 27 ] and Dietrich et al [ 12 ] developed small molecules with oral bioavailability that bind deeply in the TNF homotrimer, being able to allosterically stabilize an asymmetric complex or the trimer itself, leading to signaling inhibition. Xiao et al [ 30 ] also proposed a compound that deforms the TNF trimer upon binding, leading to deregulated signaling upon binding of the TNF trimer to TNFR1.…”

Unexpected Similarity Between HIV‐1 Reverse Transcriptase and Tumor Necrosis Factor Binding Sites Revealed by Computer Vision.

“…In absence of X-ray structures of TNF-α bound to efavirenz and delavirdine, we cannot rule out the possibility that both inhibitors bind to a different pocket than that highlighted in the current computational study. This hypothesis is however very unlikely for two reasons: (i) no other cavity than that occurring at the inner core of the multimeric TNF-α could be detected among the currently existing 33 structures available in the Protein Data Bank; (ii) all non-covalent small molecular weight inhibitors co-crystallized with TNF-α dimeric or trimeric forms [32][33][34][35] are exactly bound at the central pocket examined in this study.…”

An orally active, small-molecule TNF inhibitor that disrupts the homotrimerization interface improves inflammatory arthritis in mice

“…Moreover, the high-molecular weight biologics cannot be applicable to the central nervous system diseases associated with high TNF signaling, such as Alzheimer's disease. Several small-molecule compounds have been successful in preclinical studies, demonstrating prospects for future clinical applications (24)(25)(26)(27)(28). Therefore, small-moleculebased therapies are considered potential alternatives to TNF inhibition by biologics (29).…”