ShouTi’s Rationally Designed Small Molecules are Challenging Biologics and Peptides
Biologic and peptide therapeutics have contributed to revolutionary advances in medicine, but they may require extra steps to be shipped, stored and administered. ShouTi believes many targets addressed by those large molecules can be reached by innovative, rationally-designed, best-in-class small molecules that don’t need refrigeration or injection.
Small molecules offer substantial benefits. “Because they can be taken orally, there is potential for higher patient compliance,” Raymond Stevens, Ph.D., CEO and founder of ShouTi, told BioSpace. “Small molecules also can be designed to optimize and target distribution in the body, so they offer more flexibility than biologics.”
For ShouTi, that translates to opportunities. “Once targets are validated by a biologic, we’re excited about converting them into small molecules,” Stevens said. The company’s lead program, for example, is a small molecule GLP1 receptor agonist. The large molecule versions “included marketed peptide drugs that have validated targets in the clinic.”
Building small molecules that do the work of biologics and peptides is possible because of advances in structure-based drug discovery. ShouTi uses a cryo-electron microscope to see the atoms and, thus, the drug targets in the body. Applying machine learning to the vast quantities of scientific data available now helps researchers identify the most important interactions between a drug molecule and its target. “We then can make the smallest possible molecule that has that same function or enhanced functions,” Stevens said.
G protein-coupled receptors (GPCRs) are a focal point for ShouTi. “We only identified the structural data on this family within the past decade, and about five years ago there was a big breakthrough in the field of cryo-electron microscopy." Machine learning, which also has made great strides recently, made it possible to mine a wealth of scientific data to gain more structural insights, and therefore to possibly improve upon existing therapeutics.
ShouTi relies upon structure-based drug discovery. This approach is more efficient and rational than high throughput screening approaches, Stevens said, so molecules can be designed for more specific targeting while still having the desired binding, target engagement and safety properties.
Three years since its founding, ShouTi’s pipeline includes two clinical programs, one nearing the clinic and additional programs in discovery. “We’re quite pleased with our progress,” he shared.
The most advanced of its programs addresses pulmonary arterial hypertension, and a Phase I trial will be completed in 2022.
ShouTi's second program, for Type 2 diabetes and obesity, recently started a Phase I trial.
“We saw how GLP1 receptor peptides are changing people’s lives,” Stevens said. “GLP1 is a well-known pathway to release insulin and decrease glucagon in the body. We believe an orally-available small molecule can improve patient compliance and optimize distribution in the body.”
This program may well represent ShouTi’s biggest effort. As Stevens said, “One of the biggest global needs is around metabolic diabetes and obesity. It’s been growing steadily worldwide.”
A third program, for idiopathic pulmonary fibrosis, is in investigational new drug (IND) enabling studies.
It’s somewhat unusual for small companies to target three different therapeutic areas, but Stevens sees commonalities that override any differences. “Our pulmonary, cardiovascular and metabolic programs are all based around GPCRs, so this is the same protein target family, and they all involve chronic disease,” he said. “We think a small molecule is better because of its (greater) tissue penetration and pharmaceutical properties, and also because it can make the therapeutic more accessible to everyone in the world.
“One of the most important questions you ask yourself when you start a company is where you want to point the technology. We chose the biggest global unmet needs that we think we can address: chronic diseases of the metabolic, cardiovascular and pulmonary systems."
While building ShouTi, Stevens and his team made a conscious decision to house the technology platform in a dedicated entity called Basecamp Bio. Stevens said this decision enables the technology platform to continue to be focused and evolve, rather than risk having attention diverted as programs entered the clinic. “We also wanted to create kind of an incubator to evaluate new drug discovery targets,” he said.
Basecamp Bio represents a convergence of experimental and computational methods with the goal of pushing the boundaries of what is possible in drug discovery and development.
ShouTi is located in South San Francisco and Shanghai, with its finance and clinical operations in the U.S. and its research and discovery operations in China. “We decided on day one that we wanted to be a global company and have a commitment to global health,” Stevens said. “We don’t see ourselves as a Chinese company…or as a U.S. company. (It’s incorporated in the Cayman Islands.) We view ourselves as a global company and wanted to have a global strategy.
“The biggest challenge in building biotech companies these days is talent,” he added. “If you only look in one neighborhood, you’re going to be limited.”