A5086754286- Computational Drug Discovery Methods
- Synthesis of heterocyclic compounds
- Synthesis and Reactivity of Sulfur-Containing Compounds
- Pluripotent Stem Cells Research
- Genomics and Chromatin Dynamics
- Biomedical Ethics and Regulation
- Epigenetics and DNA Methylation
- Chemical Synthesis and Analysis
- Histone Deacetylase Inhibitors Research
- Mentoring and Academic Development
- Health and Medical Research Impacts
- Diversity and Career in Medicine
- Drug Transport and Resistance Mechanisms
- Protein Interaction Studies and Fluorescence Analysis
- Signaling Pathways in Disease
- Sulfur-Based Synthesis Techniques
- Cholinesterase and Neurodegenerative Diseases
- Quinazolinone synthesis and applications
- Mycobacterium research and diagnosis
- Free Radicals and Antioxidants
- Tuberculosis Research and Epidemiology
- Phosphodiesterase function and regulation
- Acute Myeloid Leukemia Research
- DNA and Nucleic Acid Chemistry
- Synthesis and Catalytic Reactions
Schrodinger (United States)
2022-2024
Monash University
2008-2023
KAT6A, and its paralog KAT6B, are histone lysine acetyltransferases (HAT) that acetylate H3K23 exert an oncogenic role in several tumor types including breast cancer where KAT6A is frequently amplified/overexpressed. However, pharmacologic targeting of to achieve therapeutic benefit has been a challenge. Here we describe identification highly potent, selective, orally bioavailable KAT6A/KAT6B inhibitor CTx-648 (PF-9363), derived from benzisoxazole series, which demonstrates anti-tumor...
The blood-brain barrier (BBB) plays a critical role in preventing harmful endogenous and exogenous substances from penetrating the brain. Optimal brain penetration of small-molecule central nervous system (CNS) drugs is characterized by high unbound brain/plasma ratio (Kp,uu). While various medicinal chemistry strategies silico models have been reported to improve BBB penetration, they limited application predicting Kp,uu directly. We describe physics-based computational approach, quantum...
A high-throughput screen for inhibitors of the histone acetyltransferase, KAT6A, led to identification an aryl sulfonohydrazide derivative (CTX-0124143) that inhibited KAT6A with IC50 1.0 μM. Elaboration structure-activity relationship and medicinal chemistry optimization discovery WM-8014 (97), a highly potent inhibitor (IC50 = 0.008 μM). competes acetyl-CoA (Ac-CoA), X-ray crystallographic analysis demonstrated binding Ac-CoA site. Through inhibition activity, induces cellular senescence...
A newly validated target for tuberculosis treatment is phosphopantetheinyl transferase, an essential enzyme that plays a critical role in the biosynthesis of cellular lipids and virulence factors Mycobacterium tuberculosis. The structure-activity relationships recently disclosed inhibitor, amidinourea (AU) 8918 (1), were explored, focusing on biochemical potency, determination whole-cell on-target activity active compounds, profiling selective congeners. These studies show AU moiety largely...
A high-throughput screen designed to discover new inhibitors of histone acetyltransferase KAT6A uncovered CTX-0124143 (1), a unique aryl acylsulfonohydrazide with an IC50 1.0 μM. Using this as template, we herein disclose the results our extensive structure-activity relationship investigations, which resulted in discovery advanced compounds such 55 and 80. These two represent significant improvements on recently reported prototypical lead WM-8014 (3) they are not only equivalently potent but...
Dual leucine zipper kinase (DLK), expressed primarily in neuronal cells, is a regulator of degeneration response to cellular stress from chronic disease or injury. This makes it an attractive target for the treatment neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis; injury, chemotherapy induced peripheral neuropathy. Here we describe discovery potent, selective, brain-penetrant DLK inhibitor, KAI-11101 (59). Throughout program's progression,...
Dual leucine zipper kinase (DLK), expressed primarily in neuronal cells, is a regulator of degeneration response to cellular stress from chronic disease or injury. This makes it an attractive target for the treatment neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis; injury, chemotherapy induced peripheral neuropathy. Here we describe discovery potent, selective, brain-penetrant DLK inhibitor, KAI-11101 (59). Throughout program's progression,...
Dual leucine zipper kinase (DLK), expressed primarily in neuronal cells, is a regulator of degeneration response to cellular stress from chronic disease or injury. This makes it an attractive target for the treatment neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis; injury, chemotherapy induced peripheral neuropathy. Here we describe discovery potent, selective, brain-penetrant DLK inhibitor, KAI-11101 (59). Throughout program's progression,...
Dual leucine zipper kinase (DLK), expressed primarily in neuronal cells, is a regulator of degeneration response to cellular stress from chronic disease or injury. This makes it an attractive target for the treatment neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, injury, chemotherapy-induced peripheral neuropathy. Here, we describe discovery potent, selective, brain-penetrant DLK inhibitor, KAI-11101 (59). Throughout program's progression,...
A mild, general method for the [3,3]-sigmatropic rearrangement of N,O-diacylhydroxylamines, employing a combination mild base and Lewis acid, is described. Employing stoichiometric amounts reagents with respect to substrate provides α-acyloxyamides, whereas an excess favors formation cyclic orthoamides.
Dual leucine zipper kinase (DLK), expressed primarily in neuronal cells, is a regulator of degeneration response to cellular stress from chronic disease or injury. This makes it an attractive target for the treatment neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis; injury, chemotherapy induced peripheral neuropathy. Here we describe discovery potent, selective, brain-penetrant DLK inhibitor, KAI-11101 (59). Throughout program's progression,...
The blood-brain barrier (BBB) plays a critical role in preventing harmful endogenous and exogenous substances from penetrating the brain. Optimal brain penetration of small molecule CNS drugs is characterized by high unbound brain/plasma ratio (Kp,uu). While various medicinal chemistry strategies silico models have been reported to improve BBB penetration, none were developed predict Kp,uu directly. We describe physics-based computational approach, solvation free energy calculations (energy...
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