Screening ACVR1 inhibitors on mutant and non-mutant ACVR1 DIPG cells – effectiveness may vary

Hi there! The last month of my life was taken over by making sure my PhD first year report was beautifully polished, but I have returned with results of a small compound screen: These are all compounds that Jong Fu has already tested with his assays so we know they effectively inhibit ACVR1, but I Read More …

CaMKK2 Inhibitor Series

The line of up of different inhibitor series (hinge binders) for CaMKK2 that we are currently pursuing include: furopyridine, azaindole (pyrrolopyridine), quinoline, triazolopyridazine, imidazopyrazine, pyrazolopyrimidine. Figure 1. Figure 1: CaMKK2 hinge binders As part of our structure and activity relationships (SAR), we continue to build diversity on the pyridine ring for the furopyridine series, and Read More …

Introduction to CaMKK2: Goals and previous work

The goal of the Structural Genomics Consortium (SGC) is to discover and share selective small molecule inhibitors of protein kinases. Kinases have key roles in cell signaling, regulation of cell cycle progression, metabolism and other significant biological function. Cancers, immunological and metabolic diseases, among other ailments are caused by deregulation of kinase function. Protein kinases Read More …

Current Progress on the Synthesis of CaMKK2 Inhibitors: Furopyridine Analogs

Following the successful synthesis of the furopyridine scaffold via an alternative synthetic route, conditions have been worked out to optimize yields on the synthesis of the key intermediate: 5-bromobenzofuran-3(2H)-one. Thus far the following set of analogs, Figure 1, have been generated by building diversity on the pyridine ring. These analogs together with with proposed others Read More …

Last set of DRAK2 inhibitors to be synthesized?

This is what is planned to be the last small set of compounds prepared as STK17B/DRAK2 kinase inhibitors. Here, chemical modifications are made in the “top part” of the parent compound AP-39. The goal is to evaluate the role of other functional groups such as imidazole, tetrazole, and sulfonamides (1-3). Other changes include replacement of Read More …

Presenting a poster at the annual Medical Sciences Division DPhil Day

Every summer my department holds a special mini-conference for the DPhil (aka PhD) students so that we can get to know each other and practice presenting our research. This year I took along a poster outlining my own project – Understanding the pathogenic mechanism of ACVR1 mutations in Diffuse Intrinsic Pontine Glioma – and presented Read More …

CaMKK2 Inhibitors: Building Diversity Around the Core Furopyridine Scaffold

Preparation of CaMKK2 analogs Pursuant to our aim of preparing a library of small molecule chemical probes around our most promising core scaffold, furopyridine, we sought to develop different chemistries that would allow us to achieve this objective. In the original synthetic route, 5-bromofuro[2,3-b]pyridine, 1, was able to undergo the Suzuki cross-coupling reaction to install Read More …

Are kinase DRAK2 inhibitors active against kinase AURKB in cells? Good news: NO!

The original compound donated by Pfizer PFE-PKIS 43 (thienopyrimidine scaffold), showed activity against 3 kinases greater than 70% inhibition in the KinomeSCAN at 1 µM (STK17B/DRAK2, AURKB and SRPK2). In the series of compounds recently synthesized as thienopyrimidine derivatives we seek selective and potent inhibitors for STK17B/DRAK2 only. To further identify off-target activity of these Read More …

CLK2 inhibitor candidates

In my previous post, I presented different CLK2 inhibitors (https://openlabnotebooks.org/clk-chemical-probe/), including structures, and IC50 curves that were generated using a cell target engagement assay called NanoBRET. My colleagues Carrow Wells and Julie Pickett generated these data. The BRET of NanoBRET stands for bioluminescence resonance energy transfer, and it is an in-vitro quantitative technique to identify Read More …

Synthesis of BRSK2 Compounds

BRSK2 Compounds NRF2 is a transcription factor that regulates the expression of antioxidant proteins and functions to protect against oxidative stress caused by inflammation. Under normal physiological conditions, NRF2 is degraded by KEAP1 and Cullin 3 (CUL3) through a process called ubiquitination (ubiquitin-dependent proteolysis). Following ubiquitination, it is transported to the proteasome where it is Read More …