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 …

Optimising an assay to detect alkaline phosphatase activity in C2C12 cells

I don’t just want to check whether the compounds I’m testing kill DIPG cells, I want to check that they’re doing this by altering BMP signalling too. However, I can’t do this with the DIPG cells, because if a compound does work, and kill them, there’ll be no cell left to actually measure the amount Read More …

Project Overview: Preparation of Active Chemical Probes for CAMKK2 and BRSK2

I provide herewith my first post –  A short overview of my current projects. Research at the SGC-UNC involves the preparation of active chemical probes for understudied protein kinases with the ultimate goal of designing potent small molecule inhibitors as treatment for diseases such as cancer. Kinases play critical roles in cellular signaling which controls important Read More …