Novartis Symposium: Michael Visser and Alison Narayan

Dr. Michael Visser: Illuminating the darkness…PKC inhibitors for metastatic uveal melanoma

Uveal Melanoma (UM) is the most common primary intraocular malignancy of the adult eye, with an incidence of five to six cases per million. Despite aggressive local management of primary UM, the development of metastases is common and occurs in ~50% of patients. There are currently no effective treatment options for metastatic disease and median survival is around nine months. Genetic analysis of UM samples reveals the presence of activating mutations in the Gq alpha subunits, GNAQ and GNA11.  One of the key downstream targets of the constitutively active Gq alpha subunits is the protein kinase C (PKC) signaling pathway.

We describe the discovery of NVP-LXS196, darovasertib, a potent, selective PKC inhibitor. The lead series was optimized for kinase and off target selectivity to afford a compound that is rapidly absorbed and well tolerated in pre-clinical species.  Darovasertib is currently in late-stage clinical trials to assess efficacy in 1L HLA-A2-negative metastatic uveal melanoma patients and neoadjuvant/adjuvant setting in primary UM.

Mike Visser is a group leader at Novartis Biomedical Research in Cambridge, MA. In this role, he applies his skills as a medicinal chemist in multi-disciplinary team settings in the search for new therapeutics to treat human disease. He received his undergraduate chemistry degree from Syracuse University in 1992 working in the lab of Professor Donald Dittmer. In 1997, he received a PhD from Boston College, working in the lab of Professor Amir Hoveyda in the areas of asymmetric catalysis, metathesis and organic synthesis. He then was a post-doctoral fellow in Professor Samuel Danishefsky’s lab at Memorial Sloan Kettering Cancer Center contributing to the synthesis of the core of the N-linked glycopeptide high Mannose. In 1999 Mike began his industrial career at Pfizer and later moved to Novartis in 2007.  Mike has conducted research toward new therapeutics for treating cancer, diabetes, cardiovascular disease and infectious diseases. He has worked on range of targets and modalities on projects for the treatment of cancer, including efforts which identified the Protein Kinase C inhibitor, LXS196, and Helios degrader, DKY709, which are currently being evaluated in patients.  Mike’s current research is focused on small molecule approaches to harness the body’s immune system and target approaches to fight cancer.

Professor Alison Narayan: Biocatalytic Strategies For Building Molecules

Small molecules have an outsized influence on human health as therapeutics, chemical probes, and tools for exploring biology. Yet, the full potential of these molecules is often limited by challenges in their chemical synthesis. Modern synthetic chemistry continues to advance the control of chemo-, site-, and stereoselectivity, but new strategies are still needed to make complex targets more accessible and efficient to prepare.

Biocatalysis offers a powerful solution, providing catalysts that achieve remarkable selectivity and efficiency under mild conditions. Nature’s own biosynthetic pathways, responsible for intricate metabolites such as taxol and vancomycin, illustrate this potential. Likewise, the increasing use of enzymes in industrial synthesis demonstrates the value of biocatalytic approaches. However, broader adoption in academic and industrial laboratories remains limited by the narrow range of well-characterized reactions, uncertainty in enzyme substrate scope, and challenges in integrating biocatalysis into multistep synthetic routes.

To overcome these barriers, my group employs high-throughput strategies to map sequence–function relationships and discover new enzymatic activities. In this talk, I will discuss: (1) the development of biocatalytic C–C bond-forming and C–H functionalization reactions; (2) ancestral sequence reconstruction as a strategy for building diverse and evolvable enzyme libraries; and (3) emerging platforms that aim to make biocatalysis more accessible and impactful for the broader organic chemistry community.