Compound 11 update (SNS-032 analogues)

Following previous post, https://opennotebook.thesgc.org/sns-032-analogues-update/, compound 11 was chosen to further investigate the structure activity relationships (SAR) of the oxazole ring system with the hope to enhance potency and improve selectivity towards each respective target. The criteria to pick the building blocks to further study the SAR is based on electronics, size and shape. I have Read More …

First set of selected compounds against DRAK2 kinase

Several compounds derived from thienopyrimidine scaffolds were recently synthesized to be tested as inhibitors of DRAK2/STK17B kinase. Among these, a set of 12 were selected to determine their potency as IC50 values on a DRAK2 cellular assay. These compounds have different functional groups around the phenyl ring and variation in the position of the sulfur Read More …

Developing an assay of viability in DIPG cell lines

Over the past few weeks I’ve been perfecting a method for screening a small set of therapeutic compounds on DIPG cell lines. Before starting I made sure to discuss the techniques used in other groups to make sure that I design an assay that is comparable to theirs, although I may make my own changes Read More …

SNS-032 analogues update

SNS-032 is a CDK2 inhibitor with an IC50 of 48 nM in cell-free assay and is 10 and 20-fold selective over CDK1 and CDK4 respectively (http://www.selleckchem.com/products/SNS-032.html). In my previous post (https://opennotebook.thesgc.org/introduction-to-my-kcgs-cdk-family-project/) I mention the aim to develop a narrow profile inhibitors for understudied kinase. To do so I have synthesized SNS-032 analogues since SNS-032 inhibits Read More …

Synthetic highlights for CLK inhibitors and ‘Shiny Science’

Preparation of GW807982X analogues can be find in Tavares’s patent from 2004 (WO2004/35588, 2004, A1). This involves a 4‑step synthesis starting from commercially available 3,6-dichloropyridazine (see previous blog, https://opennotebook.thesgc.org/project-overview-work-towards-a-clk-probe). From my experience in the lab, formation of the highly nitrogenated pyrazolopyridazine 3 is not a trivial step. This is probably because the formation of the charged Read More …

Synthesis of a selective inhibitor for DRAK2 kinase

Towards the SGC goal of creating a kinase chemogenomic set (KCGS) we have been receiving and profiling kinase inhibitors donated by pharmaceutical companies. One such compound is PFE-PKIS 43 (Scheme 1a). We received this compound from Pfizer and it was screened against 403 kinases at DiscoverX. This compound, originally synthesized and published as part of Read More …

Introduction to my KCGS CDK family project

At the SGC-UNC we are interested in building a set of inhibitors that “covers” the whole kinome. Here’s a reference that talks about our plans for the Kinase Chemogenomic Set (KCGS): http://journals.plos.org/plosone/article/related?id=10.1371/journal.pone.0181585. We are building the set with what we call “narrow spectrum” inhibitors – inhibitors that inhibit only a small set of kinases. To help Read More …

Optimising transfection of the C2C12 myoblast cell line

Within a month (hopefully) I’ll be convincing C2C12 myoblast cells to express all kinds of mutant ALK2 to test its activity and interactions with other proteins within the cell. I’ll be doing this by treating them so that they’ll take up pieces of circular DNA (plasmids) that express those mutant proteins (i.e. transfecting them). Seeing Read More …

Structure Activity Relationship (SAR) study to identify Nek4 inhibitors:

Hello! Recently, I co-authored a manuscript titled, “In depth analysis of kinase cross screening data to identify chemical starting points for inhibition of the Nek family of kinases” [http://pubs.rsc.org/en/content/articlelanding/2018/md/c7md00510e#!divAbstract]. As a part of this manuscript we identified several chemical starting points that can be used for the design of narrow spectrum and potent Nek kinase Read More …

Chemical probes for understudied kinases

One of the ongoing projects at SGC-UNC is the development of chemical probes for understudied kinases (e.g. MST1-4, TAOK1-3, DCAMKL1, MAP3K2 and MAP3K3). A chemical probe is defined as a small molecule that selectively and potently modulates a protein’s function. Generating chemical probes for understudied kinases is important so we can further understand the biology Read More …