The advent of precision medicine has catalyzed a sea change in biopharmaceutical research and development, leading to significant improvements in patient lives. Today’s translational research involves high-resolution and unbiased approaches to scientific discovery, asking and answering genome-level questions as to the molecular and genetic basis of disease. At a time when underlying genetics and whole genome profiling can define the best intervention points for human disease, it is unfortunate that limitations in current methods and experience can lead the biopharma community to deprioritize some of the more compelling target opportunities because of uncertainties around technical feasibility. The drug discovery approach has to adapt to accommodate the best targets andbuild entirely new suites of technologies and approaches. MOMA Therapeutics has been created to make this possible, and specifically, to discover the next generation of precision medicines by targeting molecular machines that underlie human disease.
Molecular machines are the laborers of the cell. They accomplish their tasks through coordinated, stepwise changes in their structure that generate force and motion— they are “conformationally-driven” engines fueled by the hydrolysis of ATP, the cell’s energy currency. The molecular machine protein family, which encompasses more than 400 members, governs many critical processes within cells. Examples include the DNA helicases and chromatin remodelers that control the maintenance and expression of genetic information, RNA helicases that mediate viral sensing and pattern recognition, and transporters that enable the movement of biomolecular cargo within a cell and across membranes.
Recent advances in genetics and functional genomics are illuminating crucial roles for molecular machines in areas of unmet medical need. In cancer, CRISPR screens are revealing numerous instances where mutations in a tumor drive its strict dependence on a molecular machine for growth and survival (“synthetic lethality”). Likewise, in rare genetic disorders, point mutations in the machines themselves lead to altered or insufficient function. In fact, over half of the cell’s molecular machines have been shown to harbor variations that can contribute to human disease. In some of these cases, restoration of the machine’s function provides a compelling therapeutic approach. The power of this concept is revealed by drugs that modulate the cystic fibrosis transporter, a molecular machine that when mutated, causes this disease. To date, only a handful of molecular machines have been successfully targeted by approved therapeutics (additional examples include omeprazole, which targets the H+/K+ ATPase, and etoposide, which inhibits topoisomerase II). Not only do these medicines further underscore the therapeutic potential of these enzymes, they also illustrate biopharma’s rudimentary approaches to prosecuting them – nearly all were discovered from natural products, through serendipity or without a systematic approach to interrogating the biochemistry of the proteins themselves.
Beyond a lack of systemization, the drug discovery community has also failed to develop a holistic view of these enzymes as a family, a key enablement behind the successful pursuit of other target classes like protein kinases and G-protein coupled receptors. MOMA Therapeutics has been created with the goal of establishing a platform focused on the drug discovery of molecular machines by exploiting a key vulnerability inherent to all enzymes in the class: their dependence on well-coordinated, stepwise changes in protein conformation. Our approach is based on surveying all conformational states of a molecular machine to identify small molecule binders. This will enable us to identify compounds whose action affect function by disrupting the enzyme’s ordered conformational cycle. This methodology is intentionally unbiased and designed to discover pharmacologically relevant and optimal chemistries. Importantly, this approach will be systematized across the various sub-families of molecular machines to ensure that MOMA Therapeutics grows in sophistication and efficiency over time. Using Cryo-EM to visualize protein conformations, modern chemical screens for hit generation, and emerging tools in biophysics, biochemistry and computation to characterize and evolve chemical matter, MOMA Therapeutics has a singular focus, to discover and develop innovative new medicines for patients.
To achieve these goals, we are building a team of drug discovery professionals and scientific experts that share our focus. Collectively, our leadership team has achieved numerous drug approvals and has an extensive track record of accomplishment in some of the industry’s most productive R&D organizations. MOMA Therapeutics is founded by a world-class team of academic scientists: Dorothee Kern, PhD (HHMI, Brandeis University), a world expert in protein biophysics and motion, Eva Nogales, PhD (HHMI, UC Berkeley), a pioneer in the field of Cryo-EM and structural biology, and Johannes Walter, PhD (HHMI, Harvard Medical School), a leader in the field of molecular machines and genome maintenance; they are joined by Timur Yusufzai, PhD (Entrepreneur-in-Residence at Third Rock Ventures, former Assistant Professor, Harvard Medical School), an expert on the biochemistry of molecular machines. We are also fortunate to have the financial backing of world-class biotech investors led by Third Rock Ventures and including Nextech Invest, Cormorant Asset Management, Creacion Ventures, Casdin Capital, and Rock Springs Capital, who collectively funded the company’s Series A with $86 million and will apply their experience and networks to MOMA’s effort.
Unlocking a new target class in drug discovery is no small task. It requires scientific and technological excellence. It demands a culture of focus, resilience, creativity and collaboration. Most importantly, it requires that everyone on the team – scientists, leadership, founders and investors –share a single mission: to succeed on behalf of patients. With line of sight to multiple therapeutic opportunities in the class, MOMA Therapeutics has a clear North Star, transforming the lives of patients through novel precision medicines. This is where the MOMA Therapeutics journey begins.