8fmu
From Proteopedia
Crystal structure of human Brachyury G177D variant in complex with SJF-4601
Structural highlights
DiseaseTBXT_HUMAN Thoracolumbosacral spina bifida cystica;Cervicothoracic spina bifida cystica;Lumbosacral spina bifida cystica;Cervicothoracic spina bifida aperta;Upper thoracic spina bifida aperta;Lumbosacral spina bifida aperta;Thoracolumbosacral spina bifida aperta;Cervical spina bifida cystica;Upper thoracic spina bifida cystica;Total spina bifida aperta;Chordoma;Total spina bifida cystica;Cervical spina bifida aperta;Sacral agenesis-abnormal ossification of the vertebral bodies-persistent notochordal canal syndrome. Disease susceptibility is associated with variations affecting the gene represented in this entry. Disease susceptibility is associated with variations affecting the gene represented in this entry. Susceptibility to development of chordomas is due to a T gene duplication. The disease is caused by mutations affecting the gene represented in this entry. FunctionTBXT_HUMAN Involved in the transcriptional regulation of genes required for mesoderm formation and differentiation. Binds to a palindromic site (called T site) and activates gene transcription when bound to such a site.[UniProtKB:P20293] Publication Abstract from PubMedBrachyury is an oncogenic transcription factor whose overexpression drives chordoma growth. The downmodulation of brachyury in chordoma cells has demonstrated therapeutic potential, however, as a transcription factor it is classically deemed "undruggable". Given that direct pharmacological intervention against brachyury has proven difficult, attempts at intervention have instead targeted upstream kinases. Recently, afatinib, an FDA-approved kinase inhibitor, has been shown to modulate brachyury levels in multiple chordoma cell lines. Herein, we use afatinib as a lead to undertake a structure-based drug design approach, aided by mass-spectrometry and X-ray crystallography, to develop DHC-156, a small molecule that more selectively binds brachyury and downmodulates it as potently as afatinib. We eliminated kinase-inhibition from this novel scaffold while demonstrating that DHC-156 induces the post-translational downmodulation of brachyury that results in an irreversible impairment of chordoma tumor cell growth. In doing so, we demonstrate the feasibility of direct brachyury modulation, which may further be developed into more potent tool compounds and therapies. Development of a Small Molecule Downmodulator for the Transcription Factor Brachyury.,Chase DH, Bebenek AM, Nie P, Jaime-Figueroa S, Butrin A, Castro DA, Hines J, Linhares BM, Crews CM Angew Chem Int Ed Engl. 2024 Apr 2;63(14):e202316496. doi: , 10.1002/anie.202316496. Epub 2024 Feb 28. PMID:38348945[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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