Discovery and Optimization of Potent and Orally Available CTP Synthetase Inhibitors for Use in Treatment of Diseases Driven by Aberrant Immune Cell Proliferation.

Herein, we report the discovery of a first-in-class chemotype 2-(alkylsulfonamido)thiazol-4-yl)acetamides that act as pan-selective inhibitors of cytidine 5'-triphosphate synthetase (CTPS1/2), critical enzymes in the pyrimidine synthesis pathway. Weak inhibitors identified from a high-throughput screening of 240K compounds have been optimized to a potent, orally active agent, compound , which has shown significant pharmacological responses at 10 mg/kg dose BID in a well-established animal model of inflammation.

Discovery of ASTX029, A Clinical Candidate Which Modulates the Phosphorylation and Catalytic Activity of ERK1/2.

Aberrant activation of the mitogen-activated protein kinase pathway frequently drives tumor growth, and the ERK1/2 kinases are positioned at a key node in this pathway, making them important targets for therapeutic intervention. Recently, a number of ERK1/2 inhibitors have been advanced to investigational clinical trials in patients with activating mutations in B-Raf proto-oncogene or Ras. Here, we describe the discovery of the clinical candidate ASTX029 () through structure-guided optimization of our previously published isoindolinone lead ().

Synthesis and growth-inhibitory activities of imidazo[5,1-]-1,2,3,5-tetrazine-8-carboxamides related to the anti-tumour drug temozolomide, with appended silicon, benzyl and heteromethyl groups at the 3-position.

A series of 3-(benzyl-substituted)-imidazo[5,1-]-1,2,3,5-tetrazines () and related derivatives with 3-heteromethyl groups has been synthesised and screened for growth-inhibitory activity against two pairs of glioma cell lines with temozolomide-sensitive and -resistant phenotypes dependent on the absence/presence of the DNA repair protein -methylguanine-DNA methyltransferase (MGMT). In general the compounds had low inhibitory activity with GI values >50 μM against both sets of cell lines. Two silicon-containing derivatives, the TMS-methylimidazotetrazine () and the SEM-analogue (), showed interesting differences: compound () had a profile very similar to that of temozolomide with the MGMT+ cell lines being 5 to 10-fold more resistant than MGMT- isogenic partners; the SEM-substituted compound () showed potency across all cell lines irrespective of their MGMT status.

Fragment-Based Discovery of a Potent, Orally Bioavailable Inhibitor That Modulates the Phosphorylation and Catalytic Activity of ERK1/2.

Aberrant activation of the MAPK pathway drives cell proliferation in multiple cancers. Inhibitors of BRAF and MEK kinases are approved for the treatment of BRAF mutant melanoma, but resistance frequently emerges, often mediated by increased signaling through ERK1/2. Here, we describe the fragment-based generation of ERK1/2 inhibitors that block catalytic phosphorylation of downstream substrates such as RSK but also modulate phosphorylation of ERK1/2 by MEK without directly inhibiting MEK.

Trends in use and yield of chest computed tomography with angiography for diagnosis of pulmonary embolism in a Connecticut hospital emergency department.

Rationale: We hypothesize that the ready availability of chest computed tomography (CT) scan, with angiography (CTA), for pulmonary embolism (PE) has resulted in its increased use in the emergency department (ED) with an associated decrease in positive studies.

Results: CTA for diagnosis of PE increased over 13-fold from 2000 to 2005. The diagnostic yield of CTA for PE decreased from 14% in 2000 to a mean (SD) of 7.