Paraza Pharma (Canada)

Covalent pan-TEAD inhibitors block YAP activity and demonstrate brain penetrance in a Hippo-dependent cancer model

Thijs J. Hagenbeek, Jason Zbieg, Russell Smith, Sayantanee Paul et autres

TEAD transcription factors enable the oncogenic activity of deregulated Hippo signaling and are a promising therapeutic target in oncology. Targeting the TEAD lipid pocket is an established path to inhibit the oncogenic activities of cofactors YAP and TAZ. Here we present two …

us, ca, fr (code pays fourni par la source)

Formal (4 + 1)-Cycloadditions of Donor–Acceptor Cyclobutanes and Isocyanides: Access to β-Enamino-diesters and β-Enaminoesters

Enzo Charbonneau, Jean-François Fournier, David Tong

In this work, a synthetic protocol for accessing substituted five-membered carbocyclic β-enamino-diesters from isocyanides and donor-acceptor (D-A) cyclobutanes is described. A formal (4 + 1)-cycloaddition furnishes β-enamino-diesters in up to 89% yield from various aliphatic and aromatic isocyanides. In addition, a tandem …

ca (code pays fourni par la source)

Optimization Leading to a Potent and Selective Cbl-b Inactive-State Inhibitor That Demonstrated In Vivo Efficacy

Jun Liang, Michael J. Lambrecht, Malcolm Huestis, Bingyan Zhu et autres

In the preceding work in this issue ( 10.1021/acsmedchemlett.6c00103 ), we described our initial structure–activity relationship (SAR) optimization that led to a pan-Cbl inhibitor ( 6 ) that demonstrated efficacy in a mouse CT26 syngeneic model. Unfortunately, attempts to improve TGI with …

ca, cn (code pays fourni par la source)

One or More CC Bond(s) Formed by Addition: Addition of Carbon Radicals and Electrocyclic Additions to CC Multiple Bonds

Guillaume Reynard

ca (code pays fourni par la source)

Optimization and In Vivo Characterization of a Series of Cbl-b Inactive-State Inhibitors

Michael J. Lambrecht, Jun Liang, Peter M.U. Ung, Malcolm P. Huestis et autres

Casitas B-lineage lymphoma-b (Cbl-b), an E3 ubiquitin ligase, is a key negative regulator of immune function, and its inhibition is a promising strategy for cancer immunotherapy. Here, we show the optimization of a series of inactive-state Cbl-b inhibitors to improve their potency …

ca, cn (code pays fourni par la source)

Discovery and Optimization of Orally Bioavailable Heterobifunctional Degraders of KAT2A/B for the Treatment of Cancer

James Neef, Kimberly Straley, Chinmoy Mukherjee, Amol Tipnis et autres

Using our proprietary AI/ML platform AURIGIN that maps tumor cells against normal developmental pathways, we identify targets that have been hijacked by cancerous cells to maintain a highly plastic proliferative cell state. We identified the histone acetyltransferase KAT2A as a key driver …

us, in, ca (code pays fourni par la source)

Bioactive natural products exhibiting anticancer activities

Usha Joshi, Dinesh Raj Ojha, Gorkha Raj Giri, Salyan Bhattarai et autres

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Enozertinib Is a Selective, Brain-Penetrant EGFR Inhibitor for Treating Non–Small Cell Lung Cancers with EGFR Exon 20 and Atypical Mutations

Melissa R. Junttila, Claire E. Repellin, Sumeet Salaniwal, Robert Warne et autres

EGFR mutations are common oncogenic drivers in non-small cell lung cancer (NSCLC), and approximately half of patients develop brain metastases over the course of their disease. Patients with nonclassic EGFR mutations, such as insertions in exon 20, are a high unmet need …

us, kr, in, ca (code pays fourni par la source)

Nickel‐Catalyzed P ‐Arylation of HP(= O)(R/OR) 2 Nucleophiles with (Hetero)Aryl Chlorides Enabled by DalPhos Ligation

Michael J. Cotnam, T. Kieran Redpath, Catherine Weetman, Patrick DeRoy et autres

Abstract Herein we disclose our development of broadly useful C‐P cross‐couplings of (hetero)aryl chlorides and HP(O)(R) 2 or HP(O)(OR) 2 nucleophiles, enabled by use of nickel/DalPhos‐based catalysts. These typically use 5 mol% nickel at 110 °C for 18 hours, but the feasibility …

ca, gb (code pays fourni par la source)

The Discovery of RP-2119: A Potent, Selective, and Orally Bioavailable Polθ ATPase Inhibitor

Philippe Mochirian, Robert Papp, Marie‐Claude Mathieu, Gino B. Ferraro et autres

Abstract DNA polymerase theta (Polθ) plays a critical role in repairing DNA double-strand breaks through microhomology-mediated end joining (MMEJ) and has emerged as a key synthetic lethal drug target in cancers with homologous recombination (HR) deficiencies. Its inhibition has shown a strong …

ca, us, gb, in (code pays fourni par la source)

HPLC-ESI-HRMS/MS-Based Metabolite Profiling and Bioactivity Assessment of Catharanthus roseus

Soniya Joshi, Chen Huo, Rabin Budhathoki, Anita Gurung et autres

A comprehensive metabolic profiling of Catharanthus roseus (L.) G. Don was performed using tandem mass spectrometry, along with an evaluation of the biological activities of its various solvent extracts. Among these, the methanolic leaf extract exhibited mild radical scavenging activity, low to …

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Development of Heteroaromatic Silicon Fluoride Acceptors (HetSiFAs) for 18F-Labeled Radiopharmaceuticals

Thomas A. Singleton, HyunJune Jun, Prashant S. Deore, Bren Jordan P. Atienza et autres

Abstract Silicon Fluoride Acceptors (SiFAs) enable 18F-labeling of complex peptides via isotope exchange under exceptionally mild conditions. SiFA radiopharmaceuticals have been clinically validated for diagnosing and treating cancers as tracers for positron emission tomography (PET) and radiotwin theranostics. Despite these advances, conventional …

nz, us, ca (code pays fourni par la source)