Senior Principal Scientist, Small Molecule Therapeutics

Back to jobsSenior Principal Scientist, Small Molecule TherapeuticsCambridge, MA USAApplyYour Impact at LILA We are seeking a Senior Principal Scientist, Small Molecule Therapeutics to lead the protein science and structural biology strategy supporting small molecule therapeutics across Lila’s discovery platform. This individual will oversee recombinant protein construct design and engineering, expression and purification, and structural biology workflows that enable screening, hit validation, and structure-guided drug design. Working closely with Lila’s screening, assay development, and chemistry teams, this role will help define, build, and scale internal capabilities for protein expression, purification, and structural enablement. The ideal candidate is a highly experienced protein scientist and drug discovery leader who can operate strategically while remaining deeply engaged in experimental design, vendor selection, data interpretation, and cross-functional program execution. What You'll Be Building Lead the protein science strategy for small molecule programs, ensuring timely delivery of high-quality protein reagents for screening, assay development, biophysics, crystallography, Cryo-EM, and downstream validation. Oversee recombinant protein expression and purification efforts across external partners and CROs, including vendor selection, scope definition, protocol review, troubleshooting, quality assessment, and timeline management. Develop and execute a roadmap to bring recombinant protein expression and purification capabilities in-house over time, including recommendations on infrastructure, workflows, staffing, instrumentation, and quality standards. Lead construct design and protein engineering efforts to enable soluble, stable, active, and structurally tractable protein reagents across diverse target classes. Design construct strategies including domain boundaries, truncations, tags, mutations, fusion partners, stabilizing variants, ortholog selection, and expression system selection. Partner with assay biology, screening, chemistry, computational chemistry, and translational teams to ensure protein reagents are fit-for-purpose for biochemical, biophysical, cellular, and structural applications. Lead outsourced X-ray crystallography activities, including construct and ligand complex strategy, crystallization campaign design, CRO management, structure review, and integration of structural insights into medicinal chemistry. Manage external Cryo-EM activities where appropriate, including feasibility assessment, sample preparation strategy, vendor coordination, and interpretation of structural results. Establish quality-control expectations for protein reagents, including purity, identity, activity, stability, aggregation state, binding competence, post-translational modifications, and lot-to-lot consistency. Troubleshoot protein production, purification, stability, and structural biology challenges in collaboration with internal teams and external partners. Build scalable processes for managing external protein science and structural biology work, including statements of work, decision criteria, data packages, documentation, and knowledge transfer. Serve as a subject-matter expert in protein expression, purification, construct engineering, X-ray crystallography, and structural biology across the small molecule therapeutics portfolio. Contribute to target assessment and program strategy by evaluating protein tractability, reagent feasibility, structural enablement, and risk mitigation plans. Mentor and develop future team members as internal protein science capabilities expand. Maintain awareness of emerging technologies, vendors, platforms, and best practices in recombinant protein production, structural biology, and structure-enabled drug discovery. What You'll Need to Succeed PhD in biochemistry, structural biology, molecular biology, protein engineering, or a related discipline, with 10+ years of relevant drug...