Discovery of Zilucoplan: A Complement C5 Inhibitor for Treatment of Anti-Acetylcholine Receptor (AChR) Antibody-Positive Generalized Myasthenia Gravis (gMG)
https://pubs.acs.org/doi/full/10.1021/acs.jmedchem.5c02537
Abstract
Complement component 5 (C5) is a protein in the complement cascade and a part of the innate immune system that has been clinically validated as a therapeutic target for several immune-mediated diseases including generalized myasthenia gravis (gMG). In this paper, we discuss the early discovery of zilucoplan, a macrocyclic peptide drug, which was identified via innovative extreme diversity mRNA display (Ma, Z.; Hartman, M. C. T. In Vitro Selection of Unnatural Cyclic Peptide Libraries via mRNA Display. In Ribosome Display and Related Technologies: Methods and Protocols; Douthwaite, J. A.Jackson, R. H., Eds.; Springer: New York, 2012; pp 367−390.) against C5 and approved for the treatment of gMG. We highlight the key steps and rationale behind the peptide medicinal chemistry optimization of the initial screening hits, that led to improved potency, stability, and pharmacokinetic properties.
Design, Optimization, and Biological Evaluation of First-in-Class Triple Inhibitors of SGLT1, SGLT2, and DPP4 for Type 2 Diabetes Mellitus
https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5c02225
Abstract
Type 2 diabetes care has evolved with DPP4, SGLT2, and SGLT1/2 inhibitors, but still many patients face hyperglycemia and high cardiorenal risk. Here, we designed unprecedented triple-targeted inhibitors of SGLT1/2 and DPP4 by leveraging information on binding modes of existing inhibitors. Balanced inhibition was achieved across targets while maintaining desirable pharmacokinetics with long-lasting kidney exposure. Lead compounds 64 (IC50: DPP4 = 356 nM, SGLT1 = 1.29 μM, SGLT2 = 170 nM), 99 (58 nM, 23 nM, 0.8 nM), and 101 (72 nM, 6.7 nM, 0.8 nM) induced glucosuria in nondiabetic rats. Following oral glucose challenge in Zucker diabetic rats, they demonstrated statistically superior plasma glycemic control versus SGLT2-selective inhibitor dapagliflozin and conferred a prolonged increase in active GLP-1 relative to the SGLT1/2 inhibitor sotagliflozin, implying synergistic SGLT1 and DPP4 inhibition. These results support triple-targeted inhibitors as multitarget, multiorgan drug candidates for improved glycemic control and cardiorenal benefits.
Discovery of an In Vitro and In Vivo Potent Nicotinic α7 Positive Allosteric Modulator Clinical Candidate Molecule (RGH-857)
https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5c02408
While identifying α7 nACh receptor positive allosteric modulators, a novel scaffold (1,1-dioxo-thiadiazine core) emerged from our HTS campaign, exhibiting unusually low lipophilicity compared to other screening hits. During the hit-to-lead optimization, the importance of different structural elements was evaluated. Upon combination of the best building blocks, first a lead molecule (25), then after a subsequent lead optimization, a clinical candidate compound (51, RGH-857) was identified. Having the most balanced physicochemical and in vitro pharmacological profile combined with significant in vivo efficacy in models of scopolamine-induced amnesia and natural forgetting, our results suggest that cognitive enhancement through the positive modulation of α7 nAChRs can be a viable approach to targeting cognitive decline.
BET Isoform Selectivity through Diverse Linkers for Bivalent Inhibitors: GSK785, a BRD2/4-Selective Bivalent BET Inhibitor
https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5c00622
The inhibition of the Bromodomain and Extra Terminal (BET) family of proteins has been widely studied for over a decade for its potential therapeutic benefit in cancer and immuno-inflammatory diseases. Selective inhibition within the four BET isoforms has been sought to facilitate the understanding of the individual role played by each family member and to mitigate pharmacologically driven tolerability limitations observed in the clinic for pan-BET inhibitors. Herein, we present an investigation into the potential for isoform selectivity using bivalent inhibitors with constrained linker geometries. By employing a set of conformationally restricted diamines as linkers between two BET-binding warheads, this work details the design and synthesis of two iterations of bivalent molecules. While finding the BET isoforms to be highly accommodating of bivalent molecules with diverse linker geometries, we present the discovery of 9h (GSK785), a bivalent inhibitor with an unprecedented BRD2/4-selective, BRD3 sparing profile.
DNA-Encoded Chemical Library Screening with Target Titration Analysis: DELTA
https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5c02259
DNA-encoded chemical libraries (DELs) enable the highly efficient screening of billions of small molecules for binding to a target of interest and provide valuable training data for machine learning models for virtual screening. However, DEL screening data are notoriously noisy due in large part to significant variance in the synthetic yield of library members. Here, we show an analysis from a split-sample DEL screening strategy against Bruton’s tyrosine kinase (BTK), which includes a panel of affinity selections against the target at varying concentrations and a probabilistic model to estimate the binding affinity and relative input concentrations of library members. We compared model predictions to SPR measurements of resynthesized DNA-conjugated compounds and found that this methodology yielded an improved ranking of library members by binding affinity compared to enrichment metrics. Additionally, the method successfully recovered a library member with a potent binding affinity that would not have been detected in our standard DEL selection.
