Epilogue to the Gerald Maggiora Festschrift: a tribute to an exemplary mentor, colleague, collaborator, and innovator.

In May 2022, JCAMD published a Special Issue in honor of Gerald (Gerry) Maggiora, whose scientific leadership over many decades advanced the fields of computational chemistry and chemoinformatics for drug discovery. Along the way, he has impacted many researchers in both academia and the pharmaceutical industry. In this Epilogue, we explain the origins of the Festschrift and present a series of first-hand vignettes, in approximate chronological sequence, that together paint a picture of this remarkable man.

Treatment with a VEGFR-2 antibody results in intra-tumor immune modulation and enhances anti-tumor efficacy of PD-L1 blockade in syngeneic murine tumor models.

Prolonged activation of vascular endothelial growth factor receptor-2 (VEGFR-2) due to mis-regulation of the VEGF pathway induces aberrant blood vessel expansion, which supports growth and survival of solid tumors. Therapeutic interventions that inhibit the VEGFR-2 pathway have therefore become a mainstay of cancer treatment. Non-clinical studies have recently revealed that blockade of angiogenesis can modulate the tumor microenvironment and enhance the efficacy of concurrent immune therapies.

Relationship between gene expression patterns from nasopharyngeal swabs and serum biomarkers in patients hospitalized with COVID-19, following treatment with the neutralizing monoclonal antibody bamlanivimab.

Background: A thorough understanding of a patient's inflammatory response to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection is crucial to discerning the associated, underlying immunological processes and to the selection and implementation of treatment strategies. Defining peripheral blood biomarkers relevant to SARS-CoV-2 infection is fundamental to detecting and monitoring this systemic disease. This safety-focused study aims to monitor and characterize the immune response to SARS-CoV-2 infection via analysis of peripheral blood and nasopharyngeal swab samples obtained from patients hospitalized with Coronavirus disease 2019 (COVID-19), in the presence or absence of bamlanivimab treatment.

A Phase I Study of an IDO-1 Inhibitor (LY3381916) as Monotherapy and in Combination With an Anti-PD-L1 Antibody (LY3300054) in Patients With Advanced Cancer.

LY3381916 is an orally available, highly selective, potent inhibitor of indoleamine 2,3-dioxygenase 1. This study explored the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of LY3381916 monotherapy and in combination with a programmed death-ligand 1 (PD-L1) inhibitor (LY3300054) in patients with advanced solid tumors. During dose escalation, patients received escalating doses of LY3381916 at 60-600 mg once daily (qd) and 240 mg twice daily in monotherapy (n=21) and in combination with PD-L1 inhibitor at 700 mg every 2 weeks (n=21).

Immunomodulatory Activity of a Colony-stimulating Factor-1 Receptor Inhibitor in Patients with Advanced Refractory Breast or Prostate Cancer: A Phase I Study.

Purpose: Tumor-associated macrophages correlate with increased invasiveness, growth, and immunosuppression. Activation of the colony-stimulating factor-1 receptor (CSF-1R) results in proliferation, differentiation, and migration of monocytes/macrophages. This phase I study evaluated the immunologic and clinical activity, and safety profile of CSF-1R inhibition with the mAb LY3022855.

The Folate Pathway Inhibitor Pemetrexed Pleiotropically Enhances Effects of Cancer Immunotherapy.

Purpose: Combination strategies leveraging chemotherapeutic agents and immunotherapy have held the promise as a method to improve benefit for patients with cancer. However, most chemotherapies have detrimental effects on immune homeostasis and differ in their ability to induce immunogenic cell death (ICD). The approval of pemetrexed and carboplatin with anti-PD-1 (pembrolizumab) for treatment of non-small cell lung cancer represents the first approved chemotherapy and immunotherapy combination.

Bottom-up, integrated -omics analysis identifies broadly dosage-sensitive genes in breast cancer samples from TCGA.

The massive genomic data from The Cancer Genome Atlas (TCGA), including proteomics data from Clinical Proteomic Tumor Analysis Consortium (CPTAC), provides a unique opportunity to study cancer systematically. While most observations are made from a single type of genomics data, we apply big data analytics and systems biology approaches by simultaneously analyzing DNA amplification, mRNA and protein abundance. Using multiple genomic profiles, we have discovered widespread dosage compensation for the extensive aneuploidy observed in TCGA breast cancer samples.

Identification of druggable cancer driver genes amplified across TCGA datasets.

The Cancer Genome Atlas (TCGA) projects have advanced our understanding of the driver mutations, genetic backgrounds, and key pathways activated across cancer types. Analysis of TCGA datasets have mostly focused on somatic mutations and translocations, with less emphasis placed on gene amplifications. Here we describe a bioinformatics screening strategy to identify putative cancer driver genes amplified across TCGA datasets.

3D QSAR methods: Phase and Catalyst compared.

The programs Phase and Catalyst HypoGen are compared for their performance in determining three-dimensional quantitative structure-activity relationships. Eight sets of compounds with measured activity were collected from the public literature and partitioned into suitable training and test sets by an automated procedure. A range of models is built with each program, and suggested parameter variations are investigated.

High-throughput assays for promiscuous inhibitors.

High-throughput screening (HTS) searches large libraries of chemical compounds for those that can modulate the activity of a particular biological target; it is the dominant technique used in early-stage drug discovery. A key problem in HTS is the prevalence of nonspecific or 'promiscuous' inhibitors. These molecules have peculiar properties, act on unrelated targets and can dominate the results from screening campaigns.

Identification and prediction of promiscuous aggregating inhibitors among known drugs.

Some small molecules, often hits from screening, form aggregates in solution that inhibit many enzymes. In contrast, drugs are thought to act specifically. To investigate this assumption, 50 unrelated drugs were tested for promiscuous inhibition via aggregation.

Molecular docking and high-throughput screening for novel inhibitors of protein tyrosine phosphatase-1B.

High-throughput screening (HTS) of compound libraries is used to discover novel leads for drug development. When a structure is available for the target, computer-based screening using molecular docking may also be considered. The two techniques have rarely been used together on the same target.