Small Molecule Replacements for Transcription Factors


We will leverage ML to design replacements for transcription factors implicated in longevity and cellular reprogramming. Numerous genes and transcription factors have been identified by other groups that can be used for cellular reprogramming or longevity extension (e.g. Yamanaka factors). Transcription factors exert their effects via interaction with a large set of other genes/proteins, giving them an edge over small molecule therapeutics developed with traditional, single-target approaches.

Project Team

Brennan Overhoff
Ram Samudrala
Ram Samudrala
Zack Falls
Zack Falls
William Mangione
William Mangione

Project Status

Clinical Stage
Patent Status
Patent not filed

Funding Opportunity

Opportunity type
Funding requested
Funding allocated


However, transcription factors are poor therapeutic candidates due to their ADME-T properties and likelihood to produce adverse events such as tumor formation. Our group recently developed an ML-based small molecule design pipeline which takes thousands of on-, off-, and non- targets into account simultaneously. We have already utilized this to produce attractive candidate replacements for various transcription factors implicated in aging/reprogramming such as Sox2, KLF6, Oct4, etc. We are currently looking to validate the efficacy of our most prospective designed compounds for transcription factor replacement in vivo and in vitro. Following the validation of a few top designs, we will pursue composition of matter patents for our novel chemical entities.

Project Details

We embrace a proteomic approach to drug discovery, which, in addition to giving us an advantage over competitors with single-target pipelines that do not initially account for ADME-T and off-target interactions, is necessary for modulating the myriad of genes/proteins implicated in longevity. Also, small molecules offer many advantages with respect to ADME-T and logistics that transcription factors and biologics do not. Through the NSF-sponsored I-Corps program, I interviewed numerous executives at biotech and pharmaceutical companies in longevity biotech, and found an overwhelming number of them struggling to develop biologics such as transcription factors due to poor efficacy in vivo. Solving the ADME-T problem of these biologics whilst also maintaining their in vitro efficacy by replacing them with small molecules appeared to be of utmost importance to the space.