TBXT Ligands for Chordoma: Covalent Inhibitors Targeting CYS122 Part B: Quinazolines

In this blog post, I will discuss the progress made on improving the binding affinity of new covalent quinazolines targeting CYS122, as well as some of the directions we are taking to further improve binding affinity to TBXT and reduce binding affinity towards EGFR. The synthetic work has been primarily driven by Zach and our Read More …

TBXT Ligands for Chordoma: Priority series molecules

Our chordoma research focused on developing small reversible molecules targeting the transcription factor TBXT which codes for the brachyury protein. Brachyury contains several shallow pockets, and through an x-ray crystallography fragment based approach we previously identified several series of small fragments bound to it (TBXT Fragment Hits). Our medicinal chemistry project aimed to grow the Read More …

TBXT Ligands for Chordoma: Covalent Inhibitors Targeting CYS122 Part A: Benzamides

By Zachary Davis-Gilbert, Anwar Hossain, and David H. Drewry* In conjunction with our efforts to target TBXT via non-covalent small molecules, we have also been developing covalent compounds that bind to CYS122, which has previously been shown to be accessible by afatinib (pdb code 6ZU8). In this blog post, I will discuss the progress made Read More …

Release of brachyury (TBXT) SPR Raw Data

This week we released our Surface Plasmon Resonance (SPR) data for the binding of small molecules to brachyury (gene name TBXT) on Zenodo (https://doi.org/10.5281/zenodo.6394811).  The raw data was collected by HD Biosciences as part of an ongoing campaign to identify potent ligands of this transcription factor that is critically important to chordoma cells. This upload Read More …

TBXT ligands for Chordoma: Thiazoles for pocket A’

During our initial fragment screen for brachyury, we identified two fragments that bound to pocket A’. These two structures can be found in the Protein Data Base (pdb) with codes: 5QS9 and 5QSD. To date, this site and the derivatives of these two fragments represent some of our most promising targets for targeting brachyury. In Read More …

TBXT ligands for Chordoma: lactams for pocket F

Our initial fragment screen identified four different fragments that bound to what we call site F (Figure 1) These can be found in the Protein Data Base (pdb) with these codes: 5QSA, 5QSC, 5QSI, and 5QSK. In this blog I will talk about some observations from these structures that suggest promise for this pocket, show Read More …

Brachyury (TBXT) ligands for chordoma: 1. Fragment optimization strategy 2. fragment F9000505, B-site, PDB 5QRU

Introduction In this blog post I will share details on the new molecules we have designed and synthesized or purchased based on one of our original hits from the x-ray crystallography fragment screen. The compound is called F9000505 and it is bound to pocket B. The crystal structure was deposited in the Protein Data Bank Read More …

TBXT (brachyury) and Chordoma: Project Introduction

In my Chordoma Open Lab Notebook entries, I will tell you about a project that is very important to me, targeting the transcription factor brachyury (also known as TBXT) for the rare cancer chordoma. In the coming weeks and months, the amount of science strategy, science details, and science progress shared here will rise. Today’s Read More …