Srinivas Odde

Raltegravir, elvitegravir, and metoogravir: the birth of "me-too" HIV-1 integrase inhibitors

Mercks MK-0518, known as raltegravir, has recently become the first FDA-approved HIV-1 integrase (IN) inhibitor and has since risen to blockbuster drug status. Much research has in turn been conducted over the last few years aimed at recreating but optimizing the compounds interactions with the protein. Resulting me-too drugs have shown favorable pharmacokinetic properties and appear drug-like but, as expected, most have a highly similar interaction with IN to that of raltegravir. We propose that, based upon conclusions drawn from our docking studies illustrated herein, most of these me-too MK-0518 analogues may experience a low success rate against raltegravir-resistant HIV strains. As HIV has a very high mutational competence, the development of drugs with new mechanisms of inhibitory action and/or new active substituents may be a more successful route to take in the development of second- and third-generation IN inhibitors.

HIV-1 integrase inhibitors: 2007-2008 Update

In recent years, HIV‐1 integrase (IN) has become an attractive target for designing antiretroviral agents. The first IN inhibitor approved for clinical use, raltegravir, has validated the pharmacological viability of IN inhibitors and signals the advent of a new generation of antiretroviral drugs. The development of raltegravir and other successful lead IN inhibitors has also influenced the IN inhibitor design strategy. This has led to the identification of several potent inhibitors in these last two years. Further, an increased understanding of IN structural biology has opened up novel approaches to inhibiting IN, such as targeting its multimerization or interaction with cellular cofactors. This review covers recent developments in the field of IN inhibitor design from 2007 to 2008.   © 2010 Wiley Periodicals, Inc. Med Res Rev, 30, No. 6, 890–954, 2010

Small-molecule inhibitors of APE1 DNA repair function: an overview.

APE1 is a multifaceted protein that orchestrates multiple activities in the cell, one of which is the preservation of genomic integrity; a vital process that takes place in the context of the base excision repair (BER) pathway. Studies have implicated APE1 in rendering cancerous cells less vulnerable to the effects of DNA-damaging agents that are commonly used for the treatment of cancer. Furthermore, suppression of APE1 expression in cancer cell lines is accompanied by the potentiation of the activity of cytotoxic agents. As a result, major efforts have been directed towards the identification of small-molecule inhibitors of this DNA-repair enzyme. Herein, we review all patented small-molecule APE1 inhibitors reported prior to 2011. Unfortunately, the potency and selectivity of many of the reported inhibitors were not disclosed by the original authors, and at present it is unclear if APE1 is a bona fide target for many of the purported inhibitors. Moreover, cellular activity and toxicity of many inhibitors remain to be established. Since this is the first comprehensive review of small molecule APE1 inhibitors, we present all compounds reported to inhibit APE1 activity with an IC50 value ≤ 25 μM. Efforts towards a careful validation and optimization of these compounds are warranted. Furthermore, we explore potential allosteric drug-binding sites on the protein as an alternative approach for modulating the activity of this multifunctional protein. In addition, we give an overview of APE2, as well as other APE1 homologues in some disease-causing pathogens. Finally, given the universal importance of DNA repair, as well as the considerable conservation of repair proteins across all living organisms, we propose targeting the AP endonuclease activity of pathogens by the compounds discussed in this review, thereby expanding their therapeutic potential and application.

Repositioning HIV-1 Integrase Inhibitors for Cancer Therapeutics: 1,6-Naphthyridine-7-carboxamide as a Promising Scaffold with Drug-like Properties

Among a large number of HIV-1 integrase (IN) inhibitors, the 8-hydroxy-[1,6]naphthyridines (i.e., L-870,810) were one of the promising class of antiretroviral drugs developed by Merck Laboratories. In spite of its remarkable potency and efficacy, unfortunately upon completion of phase I clinical studies, development of L-870,810 was halted. Because of its desirable pharmacological and pharmaceutical properties we were intrigued to design novel analogues of L-870,810 with goals to (1) improve upon limitations of naphthyridine-7-carboxamides as antiviral agents and (2) to reposition their use as innovative cytotoxic agents for cancer therapeutics. Herein, we report on the design and synthesis of a series of 1,6-naphthyridine-7-carboxamides with various substitutions at the 5- and 8-positions. All the new 5-substituted-8-hydroxy-[1,6]naphthyridines were potent IN inhibitors and the 5-substituted-8-amino-[1,6]naphthyridines were significantly cytotoxic. Further optimization of the 5,8-disubstituted-[1,6]naphthyridines with structural variation on 7-carboxamide delivered novel compounds with significant cytotoxicity in a panel of cancer cell lines and effective inhibition against select oncogenic kinases.

Design, Synthesis and Structure-activity Studies of Rhodanine Derivatives as HIV-1 Integrase Inhibitors

Raltegravir was the first HIV-1 integrase inhibitor that gained FDA approval for use in the treatment of HIV-1 infection. Because of the emergence of IN inhibitor-resistant viral strains, there is a need to identify innovative second-generation IN inhibitors. Previously, we identified 2-thioxo-4-thiazolidinone (rhodanine)-containing compounds as IN inhibitors. Herein, we report the design, synthesis and docking studies of a series of novel rhodanine derivatives as IN inhibitors. All these compounds were further tested against human apurinic/apyrimidinic endonuclease 1 (APE1) to determine their selectivity. Two compounds showed significant cytotoxicity in a panel of human cancer cell lines. Taken together, our results show that rhodanines are a promising class of compounds for developing drugs with antiviral and anticancer properties.

Polyketide-peroxides from a Species of Jamaican Plakortis (Porifera: Demospongiae)

A new cyclic peroxide plakortisinic acid (1), and a new ketone derivative (2), in addition to six known compounds, an α,β-unsaturated ester (3), plakortide N (4), plakortide F (5) and its free acid (6), plakortone D (7), and a furan-containing molecule (8), were isolated from a species of Plakortis from Jamaica. The structures were elucidated by interpretation of 1D and 2D NMR spectra, and mass spectrometry data and by comparison with data from the literature. Comparison between experimental and calculated optical rotations allowed the assignment of absolute configuration of 1 and 2. The isolated compounds have been evaluated for their antimicrobial, antimalarial, anticancer, anti-Mtb, and anti HIV-1 activity.

Discovery of Novel CXCR2 Inhibitors Using Ligand-Based Pharmacophore Models

The chemokine receptor CXCR2 is expressed on various immune cells and is essential for neutrophil recruitment and angiogenesis at sites of acute and chronic inflammation caused by tissue injury or infection. CXCR2 and its ligand, CXCL8, are implicated in a number of inflammation-mediated diseases such as chronic obstructive pulmonary disease, cystic fibrosis, and cancer. Though the development of CXCR2-specific small-molecule inhibitors as anti-inflammatory agents has been pursued by pharmaceutical companies within the past decade, there are currently no clinically approved CXCR2 inhibitors. A pharmacophore model based on previously reported CXCR2 antagonists was developed to screen a database of commercially available compounds. Small-molecule compounds identified from the pharmacophore screening were selected for in vitro screening in a cell-based CXCR2-mediated β-arrestin-2 recruitment assay and further characterized in several cell-based assays and lipopolysaccharide (LPS)-induced lung inflammation studies in mice. CX compounds identified from pharmacophore modeling inhibited cell migration, lung and colon cancer cell proliferation, and colony formation. Mechanistic studies of CX4152 showed that this compound inhibits CXCR2 signaling through downregulation of surface CXCR2. Additionally, CX4152 significantly inhibits CXCL8-mediated neutrophil migration and LPS-induced lung inflammation in mice. Using a CXCR2-inhibitor-based pharmacophore model, we identified a novel set of sulfonamides from a diverse library of small molecules. These compounds inhibit CXCR2/β-arrestin-2 association, cell migration and proliferation, and acute inflammation in mouse models. CX compounds identified from our pharmacophore models are potential leads for further optimization and development as anti-inflammatory and anticancer agents.