On May 26, 2020 Monte Rosa Therapeutics, a biotechnology company developing small molecules to degrade disease-related proteins, reported stealth mode revealing a $32.5 million Series A commitment from founding investor Versant Ventures and New Enterprise Associates. Monte Rosa was launched from Ridgeline, Versant’s Discovery Engine based in the Basel Technology Park (Press release, Monte Rosa Therapeutics, MAY 26, 2020, View Source [SID1234558486]). The company is now headquartered in Boston, MA, with research operations in both Boston and Basel, Switzerland.
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Monte Rosa has developed a platform to rationally design small molecules that reprogram ubiquitin ligases to eliminate disease drivers previously deemed undruggable. The platform includes computational capabilities to predict and model ligase-neosubstrate interactions and quantitative proteomics to obtain protein degradation profiles.
Expanding the horizon for cereblon reprogramming
In 2018, Monte Rosa was established in Versant’s Ridgeline laboratories in collaboration with The Institute of Cancer Research (ICR) and Cancer Research UK. Academic co-founders Rajesh Chopra, MD, and Ian Collins, PhD, are prominent leaders in the field of protein degradation.
Nicolas Thomä, PhD, a world-leading chemical and structural biologist at the Friedrich Miescher Institute in Basel, also joined Monte Rosa as scientific advisor. Dr. Thomä recently published a series of seminal papers revealing mechanistic details of cereblon-mediated protein degradation. His work demonstrated the pivotal role of a glycine loop degron on target proteins, and opened up the potential for drug discovery on many more disease-relevant targets. This work underpins Monte Rosa’s platform and approach.
"With our improved understanding of the broad potential of cereblon and other ubiquitin ligases, there is now an opportunity to eliminate major – and currently undruggable – drivers of solid tumors such as transcription factors and adaptor proteins," said Markus Warmuth, MD, CEO of Monte Rosa and a venture partner at Versant.
Developing drug candidates with novel degradation profiles
Monte Rosa has built an integrated drug discovery platform that combines one of the most diverse chemical libraries of protein degraders with in-house proteomics and structural biology capabilities. By the end of 2020, the chemical library is expected to grow to more than 10,000 structures designed for ubiquitin ligase reprogramming.
To date, several validated small molecule leads have been identified through conventional and phenotypic screens along with rational drug design. A number of these leads possess novel degradation profiles and have demonstrated in vivo efficacy across several different tumor models.
"Using this approach we can potentially design drugs for the hundreds to thousands of proteins with glycine loop degrons," said Alex Mayweg, PhD, managing director at Versant and Monte Rosa board member. "Unlike protacs, these small molecules can degrade proteins that lack classical drug-binding pockets, which include known drivers of certain forms of cancer and other serious diseases."
Operating and financing plans
Monte Rosa plans to build out its platform and concurrently develop a portfolio of drug candidates for multiple indications. One of its portfolio leads, MRT-048, has demonstrated a differentiated degradation profile and promising in vivo activity in several models of resistant breast cancer. The molecule is undergoing further preclinical development and safety testing. The company expects to file one or more IND submissions during 2021.
"Monte Rosa has built a formidable drug discovery capability and portfolio based on access to unique insights into ubiquitin ligase reprogramming," said Ali Behbahani, MD, general partner at NEA and Monte Rosa board member. "This approach is now demonstrating the potential to impact patients with intractable forms of cancer."
The company will soon launch a Series B financing to back the development of multiple clinical-stage programs. To capture the full potential of its technology platform, Monte Rosa also will explore discovery-stage pharma collaborations.