A new approach for correctors therapies

Protein misfolding and mistrafficking causes devastating diseases affecting hundreds of thousands of patients globally. Small molecule correctors are a proven therapeutic approach for such diseases, but have been mostly confined to the small subset of misfolding diseases with a few dominant mutations. The Octant Navigator platform uses Cellular Intelligence and HT-SAR to pursue multi-mutant correctors, offering new hope to treat many of these diseases.

Our Pipeline

See how we're harnessing the Navigator platform to build therapies that deliver relief to patients.

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RHO-associated autosomal dominant retinitis pigmentosa
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Fabry Disease
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p53-mutant cancer
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Melanocortin 4 receptor deficiency
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Developing correctors for misfolding diseases requires a new approach to drug discovery

The correct Cellular Context

Predicting the structure of a protein is hard. Modeling the cellular journey of a misfolded protein, how the misfolding affects the protein’s function, and the cellular response to that stress, is even harder. We’ve developed a Cellular Intelligence platform for studying protein misfolding in human cells, and to conduct high-throughput screening in that environment.

Multiplexed Read Outs

Engineering small molecule correctors requires developing a drug against multiple mutations from the start, while also optimizing the molecules for drug-like qualities. Octant’s Cellular Intelligence platform enables the multiplexed measurement of the many biological phenomena associated with protein folding and trafficking across hundreds of mutations and conditions. This enables us to fine-tune our compounds to make effective new therapies for the most patients.

Proper folding and trafficking of the mutated protein triggers a DNA barcode identifying the cell line harboring that variant. Measuring barcodes using NGS enables multiplexed testing of many variants simultaneously.

Direct-to-biology HT-SAR

Correcting misfolded proteins is a molecular dance in a crowded cellular environment. It’s difficult to progress correctors of protein misfolding because traditional methods that rely on crystal structures and biochemical binding are often not amenable to unfolded proteins. Instead, the Octant Navigator weekly synthesizes and screens thousands of chemical analogs, iterating on a molecule’s efficacy and drug-like qualities. This combines the rationality of SAR with the serendipity of phenotypic screening to enable machine learning and accelerate the empirical discovery of new corrector therapies.

HT-SAR navigates to new regions of chemical space by iterating through thousands of chemical motifs that would be left unexplored in traditional med-chem campaigns.
Steps of Cell Signaling
Steps of Transcription

Other applications of mechanism based screening

Cellular mechanisms are fundamental to many complex problems in drug discovery. Using our genetic barcoding technology we model and screen against mechanisms ranging from transcription to the signaling pathways associated with GPCRs and kinases. The Octant Navigator is well-suited to high value targets from CNS to metabolism to immunology.

Navigating Retinitis Pigmentosa

Toxic accumulation of mistrafficked rhodopsin is rescuable by small molecule correctors, sometimes called chaperones

Drug discovery in engineered cell systems

RHO-associated autosomal dominant retinitis pigmentosa (RHO-adRP) is an inherited retinal disease with no disease-modifying treatment that affects thousands of patients.

Octant is using the Navigator to design small molecule correctors that mitigate toxic accumulation of misfolded rhodopsin in the retina. We’ve engineered human cells to read out on trafficking and biophysical properties of RHO mutations, generating millions of data points from each screen that guide drug design.

Multiplexing to increase patient coverage

While most rare disease programs initially target a single mutation, our programs apply multi-mutant approaches that maximize the addressable patient population from the start. We engineer different cell lines for different mutations, each with an RNA barcode that identifies the variant. Next-generation sequencing of these barcodes enables us to find and optimize multi-mutant correctors while counter-screening against off-target mechanisms. 

Early leads for our Autosomal Dominant Retinitis Pigmentosa (adRP) program being optimized to rescue trafficking mutations tested.
HT-SAR applied to our RHO-adRP program evolves tool compounds into drug-like molecules with improved potency

HT-SAR Improves Potency and Drug-Like Properties

Nano-scale chemistry enables us to build thousands of analog molecules at a time and optimize them in learning loops. In the RHO-adRP program we iteratively built and screened 250,000+ molecules direct-to-biology, yielding thousands of structure-activity insights. We transformed early crude compounds with low potency and poor drug-like properties into potent, stable, orally available correctors that cross the blood-retinal barrier and engage the target in the retina to produce in vivo efficacy. 

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