Targeting Disease-Causing Transcription Factors with Altay Therapeutics

At Tachyon, we search for companies with the potential to address long established problems in biomedical science. One such challenge is the direct targeting of a class of proteins, known as transcription factors, using small molecules.

These proteins are key drivers of many diseases, particularly cancers, but their shape and structure make them challenging to target. When we met Dr Ali Ozes, the founder of Altay Therapeutics, we were immediately struck by his depth of knowledge, his impressive pipeline for discovering such molecules, and his plan to develop them into effective treatments for an array of debilitating diseases, starting with facioscapulohumeral muscular dystrophy (FSHD), idiopathic pulmonary fibrosis and Ewing’s sarcoma.

Transcriptions factors: their role in disease and the therapeutic challenge

Transcription factors are one of the major classes of proteins responsible for enabling and regulating the proper expression of genes. They work by binding specific locations of DNA and recruiting the molecular apparatus required for the expression of particular genes. As transcription factors can bind multiple locations in the genome, each can individually coordinate the expression of multiple genes to activate particular pathways. When a transcription factor is overactive, misregulated gene expression can occur. This can lead to an abnormal repertoire of proteins and contribute to the development of a wide array of diseases, such as cancer. For the past 20 years, it has been postulated that inhibiting transcription factors could offer a direct route towards therapeutics. Unfortunately, direct targeting of transcription factors has proved difficult until now because they tend to have few binding pockets and because they tend to alternate between structured and unstructured forms depending on their molecular interactions. Recent advances in computational predictions of protein structure, however, have provided a new opportunity to discover targetable binding pockets within these complicated and plastic molecular structures.

Advances in our understanding of transcription factors and the mechanisms by which they regulate gene expression has enabled the pursuit of several methods to create targeted therapies against them. Of these, direct targeting to prevent their binding to DNA has the advantage of being a well established and effective approach. Classically, direct targeting takes advantage of pre-identified ligand-binding pockets to develop structural derivatives of the natural ligands for these pockets. The identification of binding pockets for small molecule design has historically relied on the derivation of protein structures using x-ray crystallography. This requires obtaining the transcription factors of interest in crystal form, a technically demanding and laborious process that can take years and may not always succeed. Another challenge is that many transcription factors do not have natural ligand binding pockets, so alternative approaches need to be sought. To circumvent these difficulties, other, less specific, modalities for regulating transcription factors have been explored. These include modulating their expression, protein degradation and blocking their interactions with other proteins. Nonetheless, recent revolutionary advances in artificial intelligence have restored confidence in the possibility of targeting transcription factors directly. In particular, DeepMind’s deep learning program, AlphaFold, has demonstrated remarkable accuracy in predicting a protein’s structure from its amino acid sequence alone. As a tool, it can enable faster drug discovery and help unlock therapies for classes of proteins that have been historically hard to target, in part due to their complex structures, such as transcription factors.

Through years of research, Ali Ozes has refined his knowledge and molecular techniques to develop a platform capable of targeting transcription factors directly. He accomplishes this using three methods that work in unison to create a funnel for drug discovery:

  1. Genetic screening of known transcription factors and the prediction of biological activity around various sites on the protein. 
  2. Structural screening through molecular simulations that allow for binding pocket search and in-silico docking that can help predict the binding mode of a potential ligand with the transcription factor.
  3. Once hit molecules are identified from in-silico based screening, they are synthesized and brought to Altay’s laboratories, where they are tested in primary and secondary cell-based assays. The properties of each compound and their activities are studied in relation to the binding site of the protein to enhance the data sets used in the company’s predictive models, which further increases their success rate in future screenings. 

Using their platform, Altay has discovered three assets targeting three different transcription factors in under six months. The assets demonstrate promising in vitro and in vivo efficacy for the indications of FSHD, idiopathic pulmonary fibrosis, and Ewing’s sarcoma.

Facioscapulohumeral muscular dystrophy

FSHD is a muscular dystrophy characterized by muscle weakness affecting the neck, face, shoulders and back of patients. Although FSHD is usually not life threatening, it has a significant impact on patients’ quality of life. FSHD is driven by incomplete repression of the transcription factor DUX4, which leads to muscle cell death. Currently, FSHD has no FDA-approved treatment options, but there is one potential therapeutic in Phase III clinical trials. Fulcrum Therapeutics is currently developing a kinase inhibitor indirectly targeting DUX4, called Losmapimod. However, indirect inhibitors can often cause undesirable or secondary effects. Through its screens for small molecule binding sites within DUX4, Altay has identified a novel direct and potent inhibitor of DUX4, thereby rescuing DUX4-induced cell death.


Fibrosis is an inflammatory disease that is characterized by thickening or scarring of tissues. Pulmonary fibrosis is caused by lung scarring that makes it difficult to breathe, and is a terminal illness with no cure. Altay’s ongoing fibrosis program involves the STAT3 transcription factor, which is a driver of several inflammatory diseases, including fibrosis, scleroderma, rheumatoid arthritis, and ulcerative colitis. Currently, there are several methods of targeting STAT3 that all face similar challenges. Most importantly, the known inhibitors of STAT3 are not sufficiently specific and therefore have toxic effects. In particular, they also inhibit a closely related protein called STAT1, which is a transcription factor that is critical for immune response. Altay’s platform has identified novel small molecule binding pockets on STAT3 that are specific, demonstrating minimal STAT1 off-target inhibition and greater potency and therapeutic window than the STAT3 inhibitors that are currently in clinical trials.

Ewing’s sarcoma 

Ewing’s sarcoma is a rare cancer of the bone affecting around 250 children and adolescents each year in the United States. It is typically diagnosed around the age of 15, and it has a five-year mortality rate of about 70%. Standard treatment involves radiation, amputations, and chemotherapy. The disease is caused by a chromosomal rearrangement that results in the fusion of two genes: EWSR1 and the transcription factor-encoding gene FLI1. Altay has identified a novel inhibitor of the fusion protein that is specific to Ewing’s sarcoma cells. Currently, there are no other inhibitors in trials for this protein, marking Altay’s discovery as the first targeted therapy for Ewing’s. In addition, Altay’s inhibitor could potentially be used to target other fusions involving genes in the same family of transcription factors, such as FLI1. These fusions have been shown to drive the development of prostate and breast cancer.

Why we invested in Altay

  1. Strong team with both research and industry track-record

Dr Ali Ozes and his father, Dr Osman Ozes, make a strong duo with clear know-how in both research and industry. Dr Osman Ozes led the Pirfenidone program at Intermune, a company that was later acquired by Roche in 2014. Pirfendione was the first drug to be approved for idiopathic pulmonary fibrosis, a disease affecting around 5 million people worldwide and responsible for over 40,000 deaths in the US annually, establishing it as the most lethal non-cancer lung disease. Dr Osman’s experience in leading development for a novel drug addressing an unmet medical need will be invaluable for Altay’s own pipeline. Dr. Ali Ozes did his postdoctoral work at Johnson and Johnson (J&J) where he developed one of the first inhibitors targeting an RNA modifying enzyme. This invention has now been patented by J&J. Shortly after a two year postdoc, Ali was recruited as the lead scientist for a small startup spun out of Kevan Shokat’s group at UCSF. There, he helped develop a novel small molecule inhibitor against multiple cancers that is expected to be in the clinic next year.

  1. Addressing unmet medical needs 

Each of the first three lead candidates that Altay is pursuing may potentially represent the first therapeutic option for its indication, addressing medical needs that have to date been completely unmet. In the case of FSHD for example, Altay received funding from FSHD Global, a foundation that is dedicated to finding a cure for FSHD as soon as possible. Similarly, in the case of Ewing’s sarcoma, Altay’s inhibitor could represent the first therapeutic option for a largely lethal disease. Realizing the tremendous impact that Altay’s candidates could have on patients, and that their current leads are only three of potentially dozens of candidates, was a determining factor in our decision to support their team.

  1. Specialized platform with multiple opportunities

Altay has developed a unique and specialized platform that holds broad potential for the development of transcription factor therapeutics - a field which is just beginning to unfold new opportunities thanks to technological advancements in AI. Altay can continue to advance candidates in-house moving forward, or collaborate with pharmaceutical partners on more capital intensive prospects. Tachyon believes that Altay strikes the right balance between a team with deep expertise and a platform with many avenues.

We're excited to be joining Altay on their journey. Find out more about them here.

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