A Potent and Selective Inhibitor of Cdc42 GTPase

Cdc42, a member of the Rho family of GTPases, has been shown to play a role in cell adhesion, cytoskeletal arrangement, phagocytosis and cell motility and migration, in addition to a host of other diverse biological processes. The function of Rho-family GTPases in disease pathogenesis has been well established and identification of small, cell permeable molecules that selectively and reversibly regulate Rho GTPases is of high scientific and potentially therapeutic interest. There has been limited success in identifying inhibitors that specifically interact with small Rho family GTPases. The identified probe, ML141 (CID-2950007), is demonstrated to be a potent, selective and reversible non-competitive inhibitor of Cdc42 GTPase suitable for in vitro assays, with low micromolar potency and selectivity against other members of the Rho family of GTPases (Rac1, Rab2, Rab7). Given the highly complementary nature of the function of the Rho family GTPases, Cdc42 selective inhibitors such as those reported here should help untangle the roles of the proteins in this family

Characterization of a Cdc42 Protein Inhibitor and Its Use as a Molecular Probe

Cdc42 plays important roles in cytoskeleton organization, cell cycle progression, signal transduction, and vesicle trafficking. Overactive Cdc42 has been implicated in the pathology of cancers, immune diseases, and neuronal disorders. Therefore, Cdc42 inhibitors would be useful in probing molecular pathways and could have therapeutic potential. Previous inhibitors have lacked selectivity and trended toward toxicity. We report here the characterization of a Cdc42-selective guanine nucleotide binding lead inhibitor that was identified by high throughput screening. A second active analog was identified via structure-activity relationship studies. The compounds demonstrated excellent selectivity with no inhibition toward Rho and Rac in the same GTPase family. Biochemical characterization showed that the compounds act as noncompetitive allosteric inhibitors. When tested in cellular assays, the lead compound inhibited Cdc42-related filopodia formation and cell migration. The lead compound was also used to clarify the involvement of Cdc42 in the Sin Nombre virus internalization and the signaling pathway of integrin VLA-4. Together, these data present the characterization of a novel Cdc42-selective allosteric inhibitor and a related analog, the use of which will facilitate drug development targeting Cdc42-related diseases and molecular pathway studies that involve GTPases.This work was supported by National Science Foundation (NSF) Grant MCB0956027 and National Institutes of Health Grant R03 MH081231-01 from the Molecular Libraries Program (to A. W. N.); University of New Mexico Center for Molecular Discovery Molecular Libraries Probe Production Centers (UNMCMD MLPCN) National Institutes of Health Grants U54MH084690 and R01HL081062 (to L. A. S.); UNM National Center for Research Resources (NCRR) Grant 5P20RR016480 (to L. G. H.); National Institutes of Health Grant R21 CA170375-01 through the NCI (to A. W. N., L. G. H., and J. E. G.); National Institutes of Health Grants NS066429 and AI092130 (to T. B.); and University of Kansas Specialized Chemistry Center (KUSCC) MLPCN National Institutes of Health Grant U54HG005031 (to J. A.)

Mapping Obscured Star Formation in the Host Galaxy of FRB 20201124A

We present high-resolution 1.5--6 GHz Karl G. Jansky Very Large Array (VLA) and $\textit{Hubble Space Telescope}$ ($\textit{HST}$) optical and infrared observations of the extremely active repeating fast radio burst (FRB) FRB$\,$20201124A and its barred spiral host galaxy. We constrain the location and morphology of star formation in the host and search for a persistent radio source (PRS) coincident with FRB$\,$20201124A. We resolve the morphology of the radio emission across all frequency bands and measure a star formation rate SFR $\approx 8.9\,M_{\odot}$ yr$^{-1}$, a factor of $\approx 4-6$ larger than optically-inferred SFRs, demonstrating dust-obscured star formation throughout the host. Compared to a sample of all known FRB hosts with radio emission, the host of FRB$\,$20201124A has the most significant obscured star formation. While ${\it HST}$ observations show the FRB to be offset from the bar or spiral arms, the radio emission extends to the FRB location. We propose that the FRB progenitor could have formed $\textit{in situ}$ (e.g., a magnetar central engine born from the explosion of a massive star). It is still plausible, although less likely, that the progenitor of FRB$\,$20201124A migrated from the central bar of the host, e.g., via a runaway massive star. We further place a limit on the luminosity of a putative PRS at the FRB position of $L_{\rm 6.0 \ GHz}$$\lesssim$2.6$\times$$10^{27}$erg s$^{-1}$Hz$^{-1}$, two orders of magnitude below any PRS known to date. However, this limit is still broadly consistent with both magnetar nebulae and hypernebulae models assuming a constant energy injection rate of the magnetar and an age of$\gtrsim 10^{5}$ yr in each model, respectively.Comment: 21 pages, 6 figures, 3 tables, Submitte

Short GRB Host Galaxies I: Photometric and Spectroscopic Catalogs, Host Associations, and Galactocentric Offsets

We present a comprehensive optical and near-infrared census of the fields of 90 short gamma-ray bursts (GRBs) discovered in 2005-2021, constituting all short GRBs for which host galaxy associations are feasible ($\approx$ 60% of the total Swift short GRB population). We contribute 245 new multi-band imaging observations across 49 distinct GRBs and 25 spectra of their host galaxies. Supplemented by literature and archival survey data, the catalog contains 335 photometric and 40 spectroscopic data sets. The photometric catalog reaches $3\sigma$ depths of $\gtrsim 24-27$ mag and $\gtrsim 23-26$ mag for the optical and near-infrared bands, respectively. We identify host galaxies for 84 bursts, in which the most robust associations make up 54% (49/90) of events, while only a small fraction, 6.7%, have inconclusive host associations. Based on new spectroscopy, we determine 17 host spectroscopic redshifts with a range of $z\approx 0.15-1.6$ and find that $\approx$ 25-44% of Swift short GRBs originate from $z>1$. We also present the galactocentric offset catalog for 83 short GRBs. Taking into account the large range of individual measurement uncertainties, we find a median of projected offset of $\approx 7.9$ kpc, for which the bursts with the most robust associations have a smaller median of $\approx 4.9$ kpc. Our catalog captures more high-redshift and low-luminosity hosts, and more highly-offset bursts than previously found, thereby diversifying the population of known short GRB hosts and properties. In terms of locations and host luminosities, the populations of short GRBs with and without detectable extended emission are statistically indistinguishable. This suggests that they arise from the same progenitors, or from multiple progenitors which form and evolve in similar environments. All of the data products are available on the BRIGHT website.Comment: 53 pages, 9 figures, 6 tables, submitte

A Radio Flare in the Long-Lived Afterglow of the Distant Short GRB 210726A: Energy Injection or a Reverse Shock from Shell Collisions?

We present the discovery of the radio afterglow of the short $\gamma$-ray burst (GRB) 210726A, localized to a galaxy at a photometric redshift of $z\sim 2.4$. While radio observations commenced $\lesssim 1~$day after the burst, no radio emission was detected until $\sim11$~days. The radio afterglow subsequently brightened by a factor of $\sim 3$ in the span of a week, followed by a rapid decay (a ``radio flare''). We find that a forward shock afterglow model cannot self-consistently describe the multi-wavelength X-ray and radio data, and underpredicts the flux of the radio flare by a factor of $\approx 5$. We find that the addition of substantial energy injection, which increases the isotropic kinetic energy of the burst by a factor of $\approx 4$, or a reverse shock from a shell collision are viable solutions to match the broad-band behavior. At $z\sim 2.4$, GRB\,210726A is among the highest redshift short GRBs discovered to date as well as the most luminous in radio and X-rays. Combining and comparing all previous radio afterglow observations of short GRBs, we find that the majority of published radio searches conclude by $\lesssim 10~$days after the burst, potentially missing these late rising, luminous radio afterglows.Comment: 28 pages, 10 figures, submitted to Ap

Development of a Fluorinated Class‑I HDAC Radiotracer Reveals Key Chemical Determinants of Brain Penetrance

Despite major efforts, our knowledge about many brain diseases remains remarkably limited. Epigenetic dysregulation has been one of the few leads toward identifying the causes and potential treatments of psychiatric disease over the past decade. A new positron emission tomography radiotracer, [¹¹C]­Martinostat, has enabled the study of histone deacetylase in living human subjects. A unique property of [¹¹C]­Martinostat is its profound brain penetrance, a feature that is challenging to engineer intentionally. In order to understand determining factors for the high brain-uptake of Martinostat, a series of compounds was evaluated in rodents and nonhuman primates. The study revealed the major structural contributors to brain uptake, as well as a more clinically relevant fluorinated HDAC radiotracer with comparable behavior to Martinostat, yet longer half-life

Nasal neuron PET imaging quantifies neuron generation and degeneration

Olfactory dysfunction is broadly associated with neurodevelopmental and neurodegenerative diseases and predicts increased mortality rates in healthy individuals. Conventional measurements of olfactory health assess odor processing pathways within the brain and provide a limited understanding of primary odor detection. Quantification of the olfactory sensory neurons (OSNs), which detect odors within the nasal cavity, would provide insight into the etiology of olfactory dysfunction associated with disease and mortality. Notably, OSNs are continually replenished by adult neurogenesis in mammals, including humans, so OSN measurements are primed to provide specialized insights into neurological disease. Here, we have evaluated a PET radiotracer, [11C]GV1-57, that specifically binds mature OSNs and quantifies the mature OSN population in vivo. [11C]GV1-57 monitored native OSN population dynamics in rodents, detecting OSN generation during postnatal development and aging-associated neurodegeneration. [11C]GV1-57 additionally measured rates of neuron regeneration after acute injury and early-stage OSN deficits in a rodent tauopathy model of neurodegenerative disease. Preliminary assessment in nonhuman primates suggested maintained uptake and saturable binding of [18F]GV1-57 in primate nasal epithelium, supporting its translational potential. Future applications for GV1-57 include monitoring additional diseases or conditions associated with olfactory dysregulation, including cognitive decline, as well as monitoring effects of neuroregenerative or neuroprotective therapeutics