Senior Principal Scientist, Small Molecule Therapeutics

Lila Sciences • Cambridge, MA

1d

About The Position

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.

Requirements

• PhD in biochemistry, structural biology, molecular biology, protein engineering, or a related discipline, with 10+ years of relevant drug discovery experience; or an MS/BS with 15+ years of industry experience focused on protein chemistry and structural biology.
• Deep expertise in recombinant protein expression and purification across multiple expression systems, such as bacterial, insect, and mammalian systems.
• Demonstrated experience designing and engineering protein constructs for biochemical assays, biophysical characterization, crystallography, and/or Cryo-EM.
• Strong track record supporting small molecule drug discovery programs through high-quality protein reagents and structural biology.
• Hands-on and strategic experience with protein purification workflows, including affinity, ion exchange, size-exclusion, analytical characterization, and stability optimization.
• Experience managing external CROs or partners for protein production, purification, crystallography, or related structural biology activities.
• Strong understanding of X-ray crystallography workflows, including construct design, protein-ligand complex preparation, crystallization, data collection, structure determination, and structure interpretation.
• Ability to assess protein reagent quality and suitability using analytical and biophysical methods such as SDS-PAGE, LC-MS, SEC, SEC-MALS, DSF, DLS, SPR, ITC, MST, enzyme activity assays, or related approaches.
• Experience working cross-functionally with biology, chemistry, computational, screening, and program leadership teams.
• Demonstrated ability to define strategy, manage timelines, troubleshoot complex technical problems, and communicate recommendations clearly to scientific and non-scientific stakeholders.
• Strong scientific judgment and ability to balance speed, rigor, cost, and risk in a fast-moving discovery environment.

Nice To Haves

• Experience building or scaling internal protein science capabilities, including lab design, platform selection, instrumentation recommendations, hiring plans, workflow development, and operational standards.
• Experience with challenging drug discovery target classes, such as membrane proteins, multiprotein complexes, intrinsically disordered proteins, protein-protein interaction targets, kinases, GPCRs, and ion channels.
• Familiarity with Cryo-EM sample preparation, vendor management, data interpretation, and feasibility assessment.
• Experience integrating X-ray crystallography, Cryo-EM, computational modeling, and biophysical data into structure-guided medicinal chemistry.
• Knowledge of protein stabilization approaches, including mutagenesis, ortholog screening, consensus design, thermostabilizing mutations, fusion partners, antibody/nanobody-assisted crystallography, and ligand stabilization.
• Experience with biochemical and biophysical screening strategies such as DNA-encoded library screening, high-throughput screening, fragment-based screening, and structure-enabled hit validation.
• Familiarity with AI/ML-enabled protein design, structure prediction, construct optimization, or computational chemistry workflows.
• Experience with automation or high-throughput workflows for cloning, expression screening, purification, or protein characterization.
• Excellent written and verbal communication skills, including experience reviewing technical reports, vendor proposals, structural data, and program-facing recommendations.

Responsibilities

• 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.

Benefits

• Lila Sciences is committed to equal employment opportunity regardless of race, color, ancestry, religion, sex, national origin, sexual orientation, age, citizenship, marital status, disability, gender identity or Veteran status.

What This Job Offers

• Job Type: Full-time
• Career Level: Senior
• Education Level: Ph.D. or professional degree