Discovery of 6-Fluoro-5-{4-[(5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl]piperazin-1-yl}--methylpyridine-2-carboxamide (AZD9574): A CNS-Penetrant, PARP1-Selective Inhibitor.

PARP inhibitors have attracted considerable interest in drug discovery due to the clinical success of first-generation agents such as olaparib, niraparib, rucaparib, and talazoparib. Their success lies in their ability to trap PARP to DNA; however, first-generation PARP inhibitors were not strictly optimized for trapping nor for selectivity among the PARP enzyme family. Previously we described the discovery of the second-generation PARP inhibitor AZD5305, a selective PARP1-DNA trapper.

Multiomic profiling of breast cancer cells uncovers stress MAPK-associated sensitivity to AKT degradation.

More than 50% of human tumors display hyperactivation of the serine/threonine kinase AKT. Despite evidence of clinical efficacy, the therapeutic window of the current generation of AKT inhibitors could be improved. Here, we report the development of a second-generation AKT degrader, INY-05-040, which outperformed catalytic AKT inhibition with respect to cellular suppression of AKT-dependent phenotypes in breast cancer cell lines.

Preclinical Characterization of AZD9574, a Blood-Brain Barrier Penetrant Inhibitor of PARP1.

Purpose: We evaluated the properties and activity of AZD9574, a blood-brain barrier (BBB) penetrant selective inhibitor of PARP1, and assessed its efficacy and safety alone and in combination with temozolomide (TMZ) in preclinical models.

Experimental Design: AZD9574 was interrogated in vitro for selectivity, PARylation inhibition, PARP-DNA trapping, the ability to cross the BBB, and the potential to inhibit cancer cell proliferation. In vivo efficacy was determined using subcutaneous as well as intracranial mouse xenograft models.

Developing a digital informed consent app: opportunities and challenges of a new format to inform and obtain consent in public health research.

Background: Informed consent procedures for large population-based cohort studies should be comprehensive and easy-to-use. This is particularly challenging when participants from different socio-economic groups and multicultural ethnic backgrounds are involved. Recently, more and more studies have tried to use multimedia in informed consent procedures.

Halide Noninnocence and Direct Photoreduction of Ni(II) Enables Coupling of Aryl Chlorides in Dual Catalytic, Carbon-Heteroatom Bond-Forming Reactions.

Recent mechanistic studies of dual photoredox/Ni-catalyzed, light-driven cross-coupling reactions have found that the photocatalyst (PC) operates through either reductive quenching or energy transfer cycles. To date, reports invoking oxidative quenching cycles are comparatively rare and direct observation of such a quenching event has not been reported. However, when PCs with highly reducing excited states are used (e.