Shaughnessy Robinson

Accurate and Reliable Prediction of Relative Ligand Binding Potency in Prospective Drug Discovery by Way of a Modern Free-Energy Calculation Protocol and Force Field

Designing tight-binding ligands is a primary objective of small-molecule drug discovery. Over the past few decades, free-energy calculations have benefited from improved force fields and sampling algorithms, as well as the advent of low-cost parallel computing. However, it has proven to be challenging to reliably achieve the level of accuracy that would be needed to guide lead optimization (∼5× in binding affinity) for a wide range of ligands and protein targets. Not surprisingly, widespread commercial application of free-energy simulations has been limited due to the lack of large-scale validation coupled with the technical challenges traditionally associated with running these types of calculations. Here, we report an approach that achieves an unprecedented level of accuracy across a broad range of target classes and ligands, with retrospective results encompassing 200 ligands and a wide variety of chemical perturbations, many of which involve significant changes in ligand chemical structures. In addition, we have applied the method in prospective drug discovery projects and found a significant improvement in the quality of the compounds synthesized that have been predicted to be potent. Compounds predicted to be potent by this approach have a substantial reduction in false positives relative to compounds synthesized on the basis of other computational or medicinal chemistry approaches. Furthermore, the results are consistent with those obtained from our retrospective studies, demonstrating the robustness and broad range of applicability of this approach, which can be used to drive decisions in lead optimization.

Selective interleukin-1 receptor–associated kinase 4 inhibitors for the treatment of autoimmune disorders and lymphoid malignancy

Kelly et al. report the development of two highly selective and bioavailable small molecule IRAK4 inhibitors and show for the first time their therapeutic efficacy in autoimmune disorders and in a specific subset of diffuse large B cell lymphomas in mice.

Design of selective, ATP-competitive inhibitors of Akt.

This paper describes the design and synthesis of novel, ATP-competitive Akt inhibitors from an elaborated 3-aminopyrrolidine scaffold. Key findings include the discovery of an initial lead that was modestly selective and medicinal chemistry optimization of that lead to provide more selective analogues. Analysis of the data suggested that highly lipophilic analogues would likely suffer from poor overall properties. Central to the discussion is the concept of optimization of lipophilic efficiency and the ability to balance overall druglike propeties with the careful control of lipophilicity in the lead series. Discovery of the nonracemic amide series and subsequent modification produced an advanced analogue that performed well in advanced preclinical assays, including xenograft tumor growth inhibition studies, and this analogue was nominated for clinical development.

Recent advances in the discovery of small molecule inhibitors of interleukin-1 receptor-associated kinase 4 (IRAK4) as a therapeutic target for inflammation and oncology disorders.

IRAK4, a serine/threonine kinase, plays a key role in both inflammation and oncology diseases. Herein, we summarize the compelling biology surrounding the IRAK4 signaling node in disease, review key structural features of IRAK4 including selectivity challenges, and describe efforts to discover clinically viable IRAK4 inhibitors. Finally, a view of knowledge gained and remaining challenges is provided.

Structure-activity relationship study of 2,4-diaminothiazoles as Cdk5/p25 kinase inhibitors.

Cdk5/p25 has emerged as a principle therapeutic target for numerous acute and chronic neurodegenerative diseases, including Alzheimers disease. A structure-activity relationship study of 2,4-diaminothiazole inhibitors revealed that increased Cdk5/p25 inhibitory activity could be accomplished by incorporating pyridines on the 2-amino group and addition of substituents to the 2- or 3-position of the phenyl ketone moiety. Interpretation of the SAR results for many of the analogs was aided through in silico docking with Cdk5/p25 and calculating protein hydrations sites using WaterMap. Finally, improved in vitro mouse microsomal stability was also achieved.

Prospective Evaluation of Free Energy Calculations for the Prioritization of Cathepsin L Inhibitors

Improving the binding affinity of a chemical series by systematically probing one of its exit vectors is a medicinal chemistry activity that can benefit from molecular modeling input. Herein, we compare the effectiveness of four approaches in prioritizing building blocks with better potency: selection by a medicinal chemist, manual modeling, docking followed by manual filtering, and free energy calculations (FEP). Our study focused on identifying novel substituents for the apolar S2 pocket of cathepsin L and was conducted entirely in a prospective manner with synthesis and activity determination of 36 novel compounds. We found that FEP selected compounds with improved affinity for 8 out of 10 picks compared to 1 out of 10 for the other approaches. From this result and other additional analyses, we conclude that FEP can be a useful approach to guide this type of medicinal chemistry optimization once it has been validated for the system under consideration.

Abstract LB-112: Highly potent and selective interleukin-1 receptor-associated kinase 4 inhibitors for the therapy of lymphoid malignancies

Pathologic activation of the Toll-like receptor (TLR) pathway underlies various human disorders such as autoimmune diseases, chronic inflammatory diseases and lymphoid malignancies. Current therapy of these diseases relies on immunosuppressive or chemotherapeutic agents, but more effective therapies tailored to disease-causing mechanisms are required. The IL-1 receptor-associated kinase 4 (IRAK4), is critical to TLR signaling and is recruited to TLRs by the adapter protein MyD88. Gain-of-function MYD88 mutations are activated by IRAK4 kinase in several mature B cell malignancies, including activated B-cell-like diffuse large B cell lymphoma (ABC DLBCL). Development of selective IRAK4 kinase inhibitors has been confounded by the challenging structure of IRAK4 catalytic domain. Using structure-based drug design methodologies, we identified potent and selective IRAK4 kinase inhibitors. ABC DLBCL cell lines that specifically harbor activating MYD88 mutations are killed by these inhibitors, both in vitro and in mouse xenograft models. Gene expression profiling revealed that IRAK4 kinase inhibitors downregulated prosurvival NF-κB signatures, and cytokine analysis showed a decrease in the production of inflammatory cytokines IL-6 and IL-10. Our findings open new possibilities for the therapy of malignant diseases that rely upon IRAK4 kinase. Citation Format: Priscilla N. Kelly, Divya Chaudhary, Ryan M. Young, Art Shaffer, Shaughnessy Robinson, Donna L. Romero, Rosana Kapeller, Louis M. Staudt. Highly potent and selective interleukin-1 receptor-associated kinase 4 inhibitors for the therapy of lymphoid malignancies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-112. doi:10.1158/1538-7445.AM2014-LB-112