Clinical progress and pharmacology of small molecule bromodomain inhibitors

Bromodomains have emerged as an exciting target class for drug discovery over the past decade. Research has primarily focused on the bromodomain and extra terminal (BET) family of bromodomains, which has led to the development of multiple small molecule inhibitors and an increasing number of clinical assets. The excitement centred on the clinical potential of BET inhibition has stimulated intense interest in the broader family and the growing number of non-BET bromodomain chemical probes has facilitated phenotypic investigations, implicating these targets in a variety of disease pathways including cancer, inflammation, embryonic development and neurological disorders

Advancements in the development of non-BET bromodomain chemical probes

The bromodomain and extra terminal (BET) family of bromodomain‐containing proteins (BCPs) have been the subject of extensive research over the past decade, resulting in a plethora of high‐quality chemical probes for their tandem bromodomains. In turn, these chemical probes have helped reveal the profound biological role of the BET bromodomains and their role in disease, ultimately leading to a number of molecules in active clinical development. However, the BET subfamily represents just 8/61 of the known human bromodomains, and attention has now expanded to the biological role of the remaining 53 non‐BET bromodomains. Rapid growth of this research area has been accompanied by a greater understanding of the requirements for an effective bromodomain chemical probe and has led to a number of new non‐BET bromodomain chemical probes being developed. Advances since December 2015 are discussed, highlighting the strengths/caveats of each molecule, and the value they add toward validating the non‐BET bromodomains as tractable therapeutic targets

Alkene syn- and anti-oxyamination with malonoyl peroxides

Malonoyl peroxide [6] is an effective reagent for the syn- or anti-oxyamination of alkenes. Reaction of [6] and an alkene in the presence of O-tert-butyl-N-tosylcarbamate (R3 = CO2tBu) leads to the anti-oxyaminated product in up to 99% yield. Use of O-methyl-N-tosyl carbamate (R3 = CO2Me) as the nitrogen nucleophile followed by treatment of the product with trifluoroacetic acid leads to the syn-oxyaminated product in up to 77% yield. Mechanisms consistent with the observed selectivities are proposed

Small molecules and their roles in effective pre-clinical target validation

As demonstrated in multiple historical analyses, there are two main causes of clinical attrition; firstly drugs are not efficacious, and secondly they cause unacceptable toxicity, both of which can be the result of poor pre-clinical target validation. Target validation, one of the early stages of a drug discovery program, is the process of (in) validating a drug target to ensure it is significant to the intended disease, and unlikely to drive undesired toxicity. Target validation is vital in preventing late stage failures in the clinic and, if done effectively, can save pharmaceutical companies a great deal of time and money. As such, target validation is treated extremely seriously, as demonstrated by the formation of public - private partnerships, such as Open Targets, aimed to provide evidence of biological validity and the possible likelihood of pharmacological intervention. Central to the variety of molecular tools available for use in target validation are high quality small molecules called chemical probes

The Physical Properties of the Red Supergiant WOH G64: The Largest Star Known?

WOH G64 is an unusual red supergiant (RSG) in the Large Magellanic Cloud (LMC), with a number of properties that set it apart from the rest of the LMC RSG population, including a thick circumstellar dust torus, an unusually late spectral type, maser activity, and nebular emission lines. Its reported physical properties are also extreme, including the largest radius for any star known and an effective temperature that is much cooler than other RSGs in the LMC, both of which are at variance with stellar evolutionary theory. We fit moderate-resolution optical spectrophotometry of WOH G64 with the MARCS stellar atmosphere models, determining an effective temperature of 3400 +/- 25 K. We obtain a similar result from the star's broadband V - K colors. With this effective temperature, and taking into account the flux contribution from the aysmmetric circumstellar dust envelope, we calculate log(L/L_sun) = 5.45 +/- 0.05 for WOH G64, quite similar to the luminosity reported by Ohnaka and collaborators based on their radiative transfer modeling of the star's dust torus. We determine a radius of R/R_sun = 1540, bringing the size of WOH G64 and its position on the H-R diagram into agreement with the largest known Galactic RSGs, although it is still extreme for the LMC. In addition, we use the Ca II triplet absorption feature to determine a radial velocity of 294 +/- 2 km/s for the star; this is the same radial velocity as the rotating gas in the LMC's disk, which confirms its membership in the LMC and precludes it from being an unusual Galactic halo giant. Finally, we describe the star's unusual nebula emission spectrum; the gas is nitrogen-rich and shock-heated, and displays a radial velocity that is significantly more positive than the star itself by 50 km/s.Comment: 25 pages, 5 figures; accepted for publication in The Astronomical Journa

Alkene anti-dihydroxylation with malonoyl peroxides

Malonoyl peroxide 1, prepared in a single step from the commercially available diacid, is an effective reagent for the anti-dihydroxylation of alkenes. Reaction of 1 with an alkene in the presence of acetic acid at 40 °C followed by alkaline hydrolysis leads to the corresponding diol (35-92%) with up to 13:1 anti-selectivity. A mechanism consistent with experimental findings is proposed that accounts for the selectivity observed

The Physical Properties of Red Supergiants: Comparing Theory and Observations

Red supergiants (RSGs) are an evolved stage in the life of intermediate massive stars (than than 25 solar masses). For many years, their location in the H-R diagram was at variance with the evolutionary models. Using the MARCS stellar atmospheres, we have determined new effective temperatures and bolometric luminosities for RSGs in the Milky Way, LMC, and SMC, and our work has resulted in much better agreement with the evolutionary models. We have also found evidence of significant visual extinction due to circumstellar dust. Although in the Milky Way the RSGs contribute only a small fraction (than than 1 percent) of the dust to the interstellar medium (ISM), in starburst galaxies or galaxies at large look-back times, we expect that RSGs may be the main dust source. We are in the process of extending this work now to RSGs of higher and lower metallicities using the galaxies M31 and WLM.Comment: Invited review; to appear in Massive Stars as Cosmic Engines, IAU Symp. 250, ed. F. Bresolin, P. A. Crowther, and J. Puls (Cambridge University Press

Yellow Supergiants in the Small Magellanic Cloud (SMC): Putting Current Evolutionary Theory to the Test

The yellow supergiant content of nearby galaxies provides a critical test of massive star evolutionary theory. While these stars are the brightest in a galaxy, they are difficult to identify because a large number of foreground Milky Way stars have similar colors and magnitudes. We previously conducted a census of yellow supergiants within M31 and found that the evolutionary tracks predict a yellow supergiant duration an order of magnitude longer than we observed. Here we turn our attention to the SMC, where the metallicity is 10x lower than that of M31, which is important as metallicity strongly affects massive star evolution. The SMC's large radial velocity (~160 km/s) allows us to separate members from foreground stars. Observations of ~500 candidates yielded 176 near-certain SMC supergiants, 16 possible SMC supergiants, along with 306 foreground stars and provide good relative numbers of yellow supergiants down to 12Mo. Of the 176 near-certain SMC supergiants, the kinematics predicted by the Besancon model of the Milky Way suggest a foreground contamination of >4%. After placing the SMC supergiants on the H-R diagram and comparing our results to the Geneva evolutionary tracks, we find results similar to those of the M31 study: while the locations of the stars on the H-R diagram match the locations of evolutionary tracks well, the models over-predict the yellow supergiant lifetime by a factor of ten. Uncertainties about the mass-loss rates on the main-sequence thus cannot be the primary problem with the models.Comment: Accepted by the Ap

Red Supergiants in the Andromeda Galaxy (M31)

Red supergiants are a short-lived stage in the evolution of moderately massive stars (10-25Mo), and as such their location in the H-R diagram provides an exacting test of stellar evolutionary models. Since massive star evolution is strongly affected by the amount of mass-loss a star suffers, and since the mass-loss rates depend upon metallicity, it is highly desirable to study the physical properties of these stars in galaxies of various metallicities. Here we identify a sample of red supergiants in M31 (the most metal-rich of the Local Group galaxies) and derive their physical properties by fitting MARCS atmosphere models to moderate resolution optical spectroscopy, and from V-K photometry.Comment: Accepted for publication in the Astrophysical Journa