A molecular glue degrader of the WIZ transcription factor for fetal hemoglobin induction.

Sickle cell disease (SCD) is a prevalent, life-threatening condition attributable to a heritable mutation in ß-hemoglobin. Therapeutic induction of fetal hemoglobin (HbF) can ameliorate disease complications and has been intently pursued. However, safe and effective small-molecule inducers of HbF remain elusive. We report the discovery of dWIZ-1 and dWIZ-2, molecular glue degraders of the WIZ transcription factor that robustly induce HbF in erythroblasts. Phenotypic screening of a cereblon (CRBN)-biased chemical library revealed WIZ as a previously unknown repressor of HbF. WIZ degradation is mediated by recruitment of WIZ(ZF7) to CRBN by dWIZ-1, as resolved by crystallography of the ternary complex. Pharmacological degradation of WIZ was well tolerated and induced HbF in humanized mice and cynomolgus monkeys. These findings establish WIZ degradation as a globally accessible therapeutic strategy for SCD.

Discovery of a novel, highly potent and orally bioavailable pyrrolidinone indole series of irreversible Myeloperoxidase (MPO) inhibitors.

Myeloperoxidase (MPO) is a heme-containing peroxidase from phagocytic cells, which plays an important role in the innate immune response. The primary anti-microbial function of MPO is achieved by catalyzing the oxidation of halides by hydrogen peroxide (H2O2). Upon activation of phagocytes, MPO activity is detectable in both phagosomes and extracellularly, where it can remain or transcytose into interstitial compartments. Activated MPO leads to oxidative stress and tissue damage in many inflammatory states, including cardiovascular disease. Starting from a low molecular weight (LMW) high throughput screening (HTS) hit, here we report the discovery of a novel pyrrolidinone indole (IN-4) as a highly potent MPO inhibitor. This compound displays similar in vitro potency across peroxidation, plasma and NETosis assays. In a dilution/dialysis study, <5% of the original MPO activity was detected post-incubation of MPO with IN-4, suggesting irreversible enzyme inhibition. A fast MPO inactivation rate (kinact/Ki) and low partition ratio (k3/k4) make IN-4 kinetic properties attractive for an MPO inhibitor. This compound also displays significant selectivity over the closely related thyroid peroxidase (TPO), and is selective for extracellular MPO over intracellular (neutrophil) MPO. Moreover, IN-4 shows good exposure, low clearance and high oral bioavailability in mice, rats and dogs. The high in vitro MPO activity and high oral exposure observed with IN-4 result in a dose-dependent inhibition of MPO activity in three mouse models of inflammation. In conclusion, IN-4 is a novel, potent, mechanism-based and selective MPO inhibitor, which may be used as superior therapeutic agent to treat multiple inflammatory conditions, including cardiovascular disease.

Synthesis and Selective Functionalization of Thiadiazine 1,1-Dioxides with Efficacy in a Model of Huntington's Disease.

The scope of the acid-mediated 3-component synthesis of thiadiazines was investigated. A selective functionalization of the six-membered heterocyclic core structure was accomplished by sequential alkylations, saponifications, and coupling reactions. Several new analogs of a dihydropyrimidinone Hsp70 chaperone agonist, MAL1-271, showed promising activity in a cell based model of Huntington's disease.

N-methyldecahydroquinolines: an unexpected class of alkaloids from Amazonian poison frogs (Dendrobatidae).

The dominant alkaloids previously identified in skin extracts of Amazonian dendrobatid frogs of the genus Ameerega are histrionicotoxins and 2,5-disubstituted decahydroquinolines. Analysis of alkaloids in skin extracts of Ameerega picta from Bolivia revealed that the alkaloid 257A, previously reported as a 2,5-disubstituted decahydroquinoline, is an N-methyl-2,5-disubstituted decahydroquinoline. We characterized alkaloids of another 12 of the more than 25 species recently assigned to the genus Ameerega, and five additional N-methyldecahydroquinolines were identified. In some cases, the relative configuration of the N-methyldecahydroquinolines was determined by comparison with the N-methylated products prepared from the corresponding 2,5-disubstituted decahydroquinolines of known relative configuration. A dietary source for N-methyldecahydroquinolines is unknown; however, myrmicine ants are the likely source for the 2,5-disubstituted decahydroquinolines. The alkaloids in skin extracts of three species of another genus of Amazonian poison frog, Adelphobates, were also characterized, but N-methyldecahydroquinolines were not detected.