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NIH grant 1R44GM165171-01: A massively parallel cell-based platform for the rational discovery of molecular glues
Institute: {'code': 'GM', 'abbreviation': 'NIGMS', 'name': 'National Institute of General Medical Sciences', 'admin_org_id': '12500024', 'admin_funding_url': ''}. PI: Maxwell Aaron Sherman. Award: $349090.
Start: 2026-09-19T00:00:00.
ABSTRACT
Molecular glues represent a revolutionary approach to modulating intracellular protein-protein interactions
(PPIs). They offer potential therapeutic solutions for numerous diseases including cancer, neurodegenerative
disorders, and autoimmune diseases. However, glue discovery remains largely serendipitous due to insufficient
structural data for rational drug design. This project aims to address this challenge by developing and
commercializing Stable Binder Mutation Sequencing (SBmut-seq). SBmut-seq is an integrated computational-
experimental platform that quantitatively maps the binding energetics of protein-protein and protein-ligand-
protein interfaces with residue-level resolution. SBmut-seq combines a massively parallel yeast-2-hybrid assay
with an innovative computational algorithm that integrates population growth modeling with mass-action kinetics
to accurately infer binding affinity within cells. The rich experimental data from the assay are input to
computational algorithms that directly address key challenges in rational glue discovery such as 1) sensitive
detection of Neo-PPIs to guide target discovery, 2) accurate reconstruction of interface surfaces to guide hit
molecule identification, and 3) development of sequence-activity relationship models to guide hit-to-lead and
lead optimization. Phase I will validate SBmut-seq's ability to accurately measure binding affinities for protein-
protein and protein-ligand-protein interactions using the well-characterized HRAS::RAF1 interface and the
RAS::Cyclophilin A interaction in the presence of RMC-7977. Phase II will optimize the platform for commercial
glue discovery by enhancing detection of weak interactions, constructing an E3 ligase library for glue degrader
discovery, and developing automated analysis tools. Successful completion of this project is expected to enable
rational glue discovery for a range of targets and diseases that currently lack therapeutic options.
The career development component in this Transition Grant for New Entrepreneurs will train PI Sherman in
gaining hands-on customer discovery and business planning experience, developing a biopharma network,
enhancing business communication skills, and building drug discovery expertise. The training plan includes
didactic instruction in life sciences business models, hands-on customer discovery experience, strategic network
development, business communication skill-building, and formal drug discovery training. Implementation will
occur through structured activities including business courses, customer interviews, industry conferences, formal
investor communications, and mentored drug discovery training. Mentors Dr. Jacob Laporte and Dr. Trey Ideker
will support the career development of the PI. Dr. Laporte, an accomplished scientist-entrepreneur, will provide
entrepreneurial and business development mentorship. Dr. Ideker, a distinguished systems biology researcher,
will provide technical mentorship. This comprehensive mentoring ensures the PI develops both the scientific and
entrepreneurial acumen necessary for successful technology commercialization and career advancement.document fetched 2026-09-27 02:45