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Cellular and genetic evidence suggest that inhibition of ATAD2 could be a useful strategy to treat several types of cancer. To discover small-molecule inhibitors of the bromodomain of ATAD2, we used a fragment-based approach. Fragment hits were identified using NMR spectroscopy, and ATAD2 was crystallized with three of the hits identified in the fragment screen.

Myeloid cell leukemia 1 (Mcl-1), a member of the Bcl-2 family of proteins, is overexpressed and amplified in various cancers and promotes the aberrant survival of tumor cells that otherwise would undergo apoptosis. Here we describe the discovery of potent and selective Mcl-1 inhibitors using fragment-based methods and structure-based design. NMR-based screening of a large fragment library identified two chemically distinct hit series that bind to different sites on Mcl-1. Members of the two fragment classes were merged together to produce lead compounds that bind to Mcl-1 with a dissociation constant of

Glutamate, the major excitatory neurotransmitter, functions in the brain via activation of ligand gated cation channels and also the eight subtypes of Class C G protein-coupled metabotropic glutamate receptors (mGlus).[1] Selective allosteric modulation of mGlu5 has been shown to have potential for treatment of a variety of neurological disorders[2,3] including anxiety disorders[4,5], Parkinson’s disease[6–8], Fragile X syndrome[9] and schizophrenia.[10–14] The majority of mGlu5 negative allosteric modulators (NAMs) developed to date either contain an alkyne moiety 1–4 or employ the alkyne topology as basis for ligand design,[15] as in 5–8 (Figure 1). Only recently have mGlu5 NAM chemotypes been identified, through high-throughput screening (HTS) campaigns, that are structurally unrelated to the classical acetylenic derivatives, such as 9–12 (Figure 1).[16] Due to the prevalence of ‘molecular switch‘phenomenon in MPEP related scaffolds, our interest focused on the discovery and development of novel mGlu5 NAM chemotypes, by both HTS and Artificial Neural Network (ANN) virtual screens.

Inward rectifier potassium (Kir) channels have been postulated as therapeutic targets for several common disorders including hypertension, cardiac arrhythmias and pain. With few exceptions, however, the small-molecule pharmacology of this family is limited to nonselective cardiovascular and neurologic drugs with off-target activity toward inward rectifiers. Consequently, the actual therapeutic potential and ‘drugability’ of most Kir channels has not yet been determined experimentally. The purpose of this review is to provide a comprehensive summary of publicly disclosed Kir channel small-molecule modulators and highlight recent targeted drug-discovery efforts toward Kir1.1 and Kir2.1. The review concludes with a brief speculation on how the field of Kir channel pharmacology will develop over the coming years and a discussion of the increasingly important role academic laboratories will play in this progress.

We describe robust chemical approaches toward putative CCR5 scaffolds designed in our laboratories. Evaluation of analogues in the (125)I-[MIP-1beta] binding and Ba-L-HOS antiviral assays resulted in the discovery of 64 and 68 in the 4,4-disubstitited piperidine class H, both potent CCR5 ligands (pIC 50 = 8.30 and 9.00, respectively) and HIV-1 inhibitors (pIC 50 = 7.80 and 7.84, respectively, in Ba-L-HOS assay). In addition, 64 and 68 were bioavailable in rodents, establishing them as lead molecules for further optimization toward CCR5 clinical candidates.

A four‐step, high‐yielding, kilogram‐scale protocol to prepare aldehyde 5 is reported. The key reaction is a mild, two‐step Cu2O‐mediated decarboxylation of cyanoester 3 that proceeds in excellent yield. The general applicability of this methodology has also been explored.

New developments from our laboratories in Directed ortho (DoM) and remote (DreM) metalation reactions are presented and connections to transition metal catalyzed cross coupling and olefin metathesis processes are described.

The oxygen-rich heterocyclic compound 1-which was proposed to be the structure of plicadin, the alleged naturally occurring coumestan from the herb Psoralea plicata-was synthesized by the rational combinations of directed ortho and remote metalation reactions with cascades of Negishi, Sonogashira, Castro-Stephens, and carbamoyl Baker-Venkataraman reactions.

Drug discovery programs increasingly are focusing on allosteric modulators as a means to modify the activity of G protein-coupled receptor (GPCR) targets. Allosteric binding sites are topographically distinct from the endogenous ligand (orthosteric) binding site, which allows for co-occupation of a single receptor with the endogenous ligand and an allosteric modulator that can alter receptor pharmacological characteristics. Negative allosteric modulators (NAMs) inhibit and positive allosteric modulators (PAMs) enhance the affinity and/or efficacy of orthosteric agonists. Established approaches for estimation of affinity and efficacy values for orthosteric ligands are not appropriate for allosteric modulators, and this presents challenges for fully understanding the actions of novel modulators of GPCRs. Metabotropic glutamate receptor 5 (mGlu(5)) is a family C GPCR for which a large array of allosteric modulators have been identified. We took advantage of the many tools for probing allosteric sites on mGlu(5) to validate an operational model of allosterism that allows quantitative estimation of modulator affinity and cooperativity values. Affinity estimates derived from functional assays fit well with affinities measured in radioligand binding experiments for both PAMs and NAMs with diverse chemical scaffolds and varying degrees of cooperativity. We observed modulation bias for PAMs when we compared mGlu(5)-mediated Ca(2+) mobilization and extracellular signal-regulated kinase 1/2 phosphorylation data. Furthermore, we used this model to quantify the effects of mutations that reduce binding or potentiation by PAMs. This model can be applied to PAM and NAM potency curves in combination with maximal fold-shift data to derive reliable estimates of modulator affinities.

We recently described ( J. Med. Chem. 2008 , 51 , 6538 - 6546 ) a novel class of CCR5 antagonists with strong anti-HIV potency. Herein, we detail SAR converting leads 1 and 2 to druglike molecules. The pivotal structural motif enabling this transition was the secondary sulfonamide substituent. Further fine-tuning of the substituent pattern in the sulfonamide paved the way to enhancing potency and bioavailability and minimizing hERG inhibition, resulting in discovery of clinical compound 122 (GSK163929).

The renal outer medullary potassium (K+) channel, ROMK (Kir1.1), is a putative drug target for a novel class of loop diuretic that would lower blood volume and pressure without causing hypokalemia. However, the lack of selective ROMK inhibitors has hindered efforts to assess its therapeutic potential. In a high-throughput screen for small-molecule modulators of ROMK, we previously identified a potent and moderately selective ROMK antagonist, 7,13-bis(4-nitrobenzyl)-1,4,10-trioxa-7,13-diazacyclopentadecane (VU590), that also inhibits Kir7.1. Because ROMK and Kir7.1 are coexpressed in the nephron, VU590 is not a good probe of ROMK function in the kidney. Here we describe the development of the structurally related inhibitor 2,2′-oxybis(methylene)bis(5-nitro-1H-benzo[d]imidazole) (VU591), which is as potent as VU590 but is selective for ROMK over Kir7.1 and more than 65 other potential off-targets. VU591 seems to block the intracellular pore of the channel. The development of VU591 may enable studies to explore the viability of ROMK as a diuretic target.

New developments from our laboratories in Directed ortho (DoM) and remote (DreM) metalation reactions are presented and connections to transition metal catalyzed cross coupling and olefin metathesis processes are described.

The renal outer medullary potassium channel (ROMK) is expressed in the kidney tubule and critically regulates sodium and potassium balance. The physiological functions of other inward rectifying K(+) (Kir) channels expressed in the nephron, such as Kir7.1, are less well understood in part due to the lack of selective pharmacological probes targeting inward rectifiers. In an effort to identify Kir channel probes, we performed a fluorescence-based, high-throughput screen (HTS) of 126,009 small molecules for modulators of ROMK function. Several antagonists were identified in the screen. One compound, termed VU590, inhibits ROMK with submicromolar affinity, but has no effect on Kir2.1 or Kir4.1. Low micromolar concentrations inhibit Kir7.1, making VU590 the first small-molecule inhibitor of Kir7.1. Structure-activity relationships of VU590 were defined using small-scale parallel synthesis. Electrophysiological analysis indicates that VU590 is an intracellular pore blocker. VU590 and other compounds identified by HTS will be instrumental in defining Kir channel structure, physiology, and therapeutic potential.

Die sauerstoffreiche heterocyclische Verbindung 1 wurde durch eine Kombination gezielter Metallierungen mit einer Kaskadenreaktion bestehend aus Negishi-, Sonogashira-, Castro-Stephens- und Carbamoyl-Baker-Venkataraman-Reaktionen synthetisiert. Die Struktur von 1 entspricht dem Strukturvorschlag fur Plicadin, einem aus dem Heilkraut Psoraleaplicata isolierten Cumestan.

A four‐step, high‐yielding, kilogram‐scale protocol to prepare aldehyde 5 is reported. The key reaction is a mild, two‐step Cu2O‐mediated decarboxylation of cyanoester 3 that proceeds in excellent yield. The general applicability of this methodology has also been explored.

[reaction: see text] Intramolecular Heck and ring-closing metathesis reactions on key intermediates 10 and 15, respectively, provide efficient entries into seco-C/D ring analogues of Ergot alkaloids 12 and 16, compounds of potential synthetic and biological interest.

The oxygen-rich heterocyclic compound 1-which was proposed to be the structure of plicadin, the alleged naturally occurring coumestan from the herb Psoralea plicata-was synthesized by the rational combinations of directed ortho and remote metalation reactions with cascades of Negishi, Sonogashira, Castro-Stephens, and carbamoyl Baker-Venkataraman reactions.

Myeloid cell leukemia 1 (Mcl-1), a member of the Bcl-2 family of proteins, is overexpressed and amplified in various cancers and promotes the aberrant survival of tumor cells that otherwise would undergo apoptosis. Overexpression of Mcl-1 is also a resistance mechanism that prevents tumor cells from being effectively treated by existing chemotherapies. Thus, inhibition of Mcl-1 is a promising therapeutic strategy for the treatment of cancer. However, Mcl-1 exerts its effects through protein-protein interactions and is thought to be very challenging to target with small molecules. Here we describe the discovery of potent and selective Mcl-1 inhibitors using fragment-based methods and structure-based design. From an NMR-based screen of a large fragment library, over 130 hits were identified. Two distinct chemical hit series were found that bind to two different sites on Mcl-1 as revealed by NMR-derived model structures. Members of the two fragment classes were merged together to produce compounds that bind to Mcl-1 with greater than two orders of magnitude improved binding affinity. Structures of these compounds when complexed to Mcl-1 were obtained by X-ray crystallography and provide detailed information about the molecular recognition involved in small-molecule binding to Mcl-1. Lead compounds exhibited a dissociation constant of Citation Format: Taekyu Lee, Anders Friberg, Dominico Vigil, Bin Zhao, R. Nathan Daniels, Jason P. Burke, Pedro M. Garcia-Barrantes, DeMarco Camper, Brian A. Chauder, Edward T. Olejniczak, Stephen W. Fesik. Discovery of potent and selective Mcl-1 inhibitors using fragment-based methods and structure-based design. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2350. doi:10.1158/1538-7445.AM2013-2350

The renal outer medullary potassium channel, ROMK, critically regulates salt and water balance and may be a drug target for a novel class of diuretic. However, the molecular pharmacology of the inward rectifier potassium channel family is virtually undeveloped, precluding assessment of ROMK's therapeutic potential. We therefore performed a high-throughput screen of approximately 225,000 small molecules for modulators of ROMK function, from which several novel antagonists were identified. One compound, termed VU590, inhibits ROMK with a half-inhibition concentration (IC50) of 300 nM, has no effect on Kir2.1 or Kir4.1, but inhibits Kir7.1 at low micromolar concentrations. Two structurally related compounds were identified in the screen, but were found to be comparatively weak ROMK inhibitors. Using a molecular mechanics-based knowledge of VU590, medicinal chemistry was employed to improve the potency of one compound 33-fold (IC50 from 8 μM to 240 nM). This novel probe, termed VU591, is highly selective for ROMK over Kir2.1, Kir2.3, Kir4.1, Kir6.2/SUR1B, Kir7.1 and a panel of more than 65 other potential off-targets, including voltage-gated sodium and calcium channels and hERG. Functional studies suggest the VU591 binding site is located in the cytoplasmic pore of ROMK. VU591 will be instrumental in mapping the location and topographical features of this selective binding site and could pave the way for animal studies assessing the therapeutic potential of ROMK.