Our Science

In general, historical drug discovery methods have viewed proteins as static entities. In reality, proteins are dynamic and interact with the environment around them, undergoing conformational transformations as they exert their function. As universal building blocks of life, they are guided by laws of thermodynamics, physical laws regulating how proteins fold, function and move as they travel through space and time. At Congruence, we model protein dynamics and surface topology features to rationally design small molecule stabilizers which can revert disease states.

Learn More About Our Science:

The Revenir™ Product Engine

We have created a purpose-built computational drug discovery engine called Revenir™, which captures the biophysical changes caused by mutations in proteins.  By examining surface features and numerous biophysical descriptors of both the mutated and wild-type proteins, we build an understanding of that defect and how to correct it.

Reveal

By modeling protein dynamics in new ways, we reveal hidden features on proteins

Dynamic Pocket Hunting

Reproducibly capture allosteric and cryptic pockets with the potential to revert the disease state

Achieve Congruence

Apply real-time ligand-based correction to predict small molecule hits with the potential to correct the disease state

Test

Compound predicted by Revenir™ seamlessly progress from the dry lab to the wet lab for Hit-Lead-Generation

Advantages of Revenir™

The Revenir™ Engine significantly improves on the historical drug discovery process.

Avoids need for high throughput screening

Rapid Identification of Functional Pockets

Robust Identification of Novel Chemical Matter

Unprecedented Hit Rates

Reduction in Time and Cost

Pipeline

Congruence’s pipeline represents both first-in-class and best-in-class potential to address significant
unmet medical needs in a number of high value indications.

CGX-926 is an orally-active, small molecule corrector of the melanocortin-4-receptor (MC4R), a genetically validated target regulating feeding behavior. MC4R partial loss of function mutations lead to MC4R deficiency (MC4R-d) due to receptor misfolding and disrupted trafficking to the cell surface. CGX-925 aims to correct this misfolding and trafficking, thereby addressing the severe hyperphagia and weight gain that are the main clinical manifestations of the disease.

There is no approved therapy for MC4R-D. MC4R agonists such as setmelanotide address obesity in patients affected by a deficiency of ligand in the same pathway but upstream of the MC4R receptor. In contrast, CGX-926 addresses obesity in a distinct manner by correcting receptor misfolding. The scientific literature indicates that MC4R-d is the single most common genetic risk factor of early onset obesity, several times more prevalent than diseases associated with deficiency of ligand.

Congruence believes that CGX-926 is the first MC4R-D corrector to enter the clinic. The Company will commence clinical trials in early 2026.

Congruence is pursuing a dual strategy for the potential treatment of GBA-Parkinson’s disease. The most advanced program consists of a series of orally-active and brain-penetrant small molecule pharmacological activators of GCase that restore lysosomal glucocerebrosidase (GCase) activity. The second program consists of a series of small molecule correctors that have additional activity of correcting protein misfolding.

Glucocerebrosidase (GCase) is a lysosomal enzyme which plays a key role in glycosphingolipid homeostasis. Mutations of the GBA1 gene, which encode GCase, represent the most common genetic risk factor for Parkinsons Disease (GBA-PD). GBA-PD patients have an earlier onset of the disease, progress more rapidly and have a higher burden of non-motor symptoms. GBA1 mutations lead to misfolding of GCase in the endoplasmic reticulum (ER) and hinder its proper trafficking, resulting in diminished lysosomal GCase activity. GCase deficiency contributes to GBA-PD pathogenesis by promoting alpha-synuclein aggregation and disrupting lipid homeostasis, ultimately triggering neurodegeneration and neuroinflammation.

There is no approved therapy for GBA-PD. The scientific literature indicates that GBA-PD affects ~100,000 patients in the US.
Congruence has received a research grant of $5 million dollars from The Michael J. Fox Foundation for Parkinson’s Research (MJFF) to advance its GCase-targeting small molecules for GBA1 Parkinson’s disease.

Alpha-1 antitrypsin deficiency (AATD) is caused by mutations in the SERPINA1 gene, leading to lower levels of circulating AAT in the blood and the build-up of toxic polymerized mutant protein in the liver. AATD ultimately leads to the development of lung diseases such as emphysema and liver conditions including fibrosis in affected individuals. The vast majority of AATD patients have two copies of the PiZ variant (PiZZ) of the gene. The US prevalence of AATD is estimated to be ~80,000 –to 100,000 patients.

In preclinical studies, Congruence’s orally active small molecule pharmacological correctors of AAT increase secretion of functional AAT and also reduce build-up of polymerized mutant protein in vitro and in vivo. AAT augmentation therapy, the only approved treatment, remains inadequate for the majority of patients.

In December 2024, Congruence entered into a research collaboration agreement with Ono Pharmaceutical Co., Ltd. (Ono) to discover novel small molecule correctors against multiple protein targets in the oncology area by leveraging its proprietary drug discovery platform, Revenir™.  Once the discovery effort advances to a prespecified stage, Ono has the option to acquire exclusive worldwide rights to further develop and commercialize small molecule correctors generated during the collaboration.

Congruence has entered into a research collaboration with a large pharmaceutical company to leverage its proprietary drug discovery platform, Revenir™ to discover small molecule correctors for a validated target in metabolic disease.

Preclinical Results Support our Expanding Pipeline

CGX-926, an MC4R corrector for MC4R-deficient severe obesity

  • MC4R-d the most common cause of monogenic obesity, is associated with severe hyperphagia and obesity, affecting ~100,000 patients in the US.
  • MC4R-d is caused by heterozygous and homozygous partial loss-of-function mutations in MC4R that lead to receptor misfolding and impaired trafficking to the cell surface of neurons in the paraventricular nucleus of the hypothalamus.
  • CGX-926 is an orally active, small-molecule corrector that restores proper folding, trafficking, and function of mutated MC4R, addressing the root cause of the disease.
  • CGX-926 reduces body weight and hyperphagia in a mouse MC4R-d model of obesity and has the potential to address the key clinical manifestations of MC4R-d in human patients.

Targeting GCase for Parkinson’s Disease

  • Heterozygous mutations in the GBA1 gene, which encodes glucocerebrosidase (GCase), are the most common genetic risk factor for Parkinson’s disease, with a US prevalence of ~100,000 patients.
  • GBA1 mutations (including L444P, N370S and E326K) cause GCase misfolding and lysosomal GCase deficiency, which disrupt lipid homeostasis, leading to accumulation and aggregation of alpha-synuclein in dopaminergic neurons.
  • Congruence has discovered a series of orally active and brain-penetrant small-molecule pharmacological activators of GCase (e.g., CO-1) that activate lysosomal GCase activity in patient-derived dopaminergic neurons and in a mouse GBA-1 mutant animal model.
  • GCase activators and correctors discovered by Congruence have the potential to be disease-modifying and to slow progression of GBA-PD.

A1AT Correctors for A1AT Deficiency (AATD)

  • Homozygous mutations (E242K) in the SERPINA1 gene, which encodes alpha-1 antitrypsin (A1AT), lead to AATD, affecting ~80,000 to 100,000 patients in the US and causing both liver and lung disease.
  • Mutant A1AT protein (Z-AAT) is misfolded and polymerizes in hepatocytes, driving liver disease, while decreased circulating Z-AAT renders the lung susceptible to elastin breakdown and causes lung disease.
  • Congruence has discovered orally active small-molecule A1AT correctors (e.g., CO-2) that stabilize mutant Z-AAT, prevent its polymerization in hepatocytes, and increases secretion of functional Z-AAT in plasma in cellular assays and a mouse transgenic model of AATD.
  • A1AT correctors discovered by Congruence have the potential to decrease the risk of liver fibrosis and lung emphysema in patients with AATD.

Publications