Turn proteins into structured data and help discover new therapeutics. About Leash Biosciences At Leash Bio, we are unleashing the power of machine learning to solve medicinal chemistry and create new therapies for devastating diseases.

Description Department:

Small Molecule Drug Discovery (SMDD) Reports to:

Senior Director, Small Molecule Drug Discovery Level:

Scientist or Senior Scientist (commensurate with experience) The Position The molecules we find via DEL screening are only as good as the targets we put in front of them. In SMDD, structure-enabled drug discovery starts with protein - and it starts with you. We are looking for a hands-on protein biochemist to own the large-scale production and characterization of high-quality, intracellular protein targets that fuel our hit-finding, biophysics, and structural biology efforts. You will generate milligram quantities of challenging intracellular proteins and multi-subunit complexes from mammalian and baculovirus expression systems, purify them to the homogeneity that downstream science demands, and rigorously characterize them so that every reagent leaving your bench is fit for purpose. Your protein will directly enable DEL screens, SPR campaigns, SAR cycles, crystallography, and cryo-EM - the experiments that turn targets into structures and structures into medicines. This is a bench-forward role for a scientist who takes pride in reagent quality, thrives on difficult targets, and wants their work to be the foundation that an entire discovery program is built on. In this role, you will: Design and execute purification strategies for intracellular proteins, domains, and multi-subunit complexes expressed in mammalian (Expi293 / BacMam) and baculovirus-insect (Tni) systems, at scales from screening (sub-liter) to structural and biophysics campaigns (multi-liter). Operate and develop methods on Ä

KTA FPLC

platforms across affinity, ion exchange, hydrophobic interaction, and size-exclusion chromatography to deliver protein of defined purity, stoichiometry, and stability. Characterize identity, purity, oligomeric state, and homogeneity using

SEC-MALS

as a primary readout, complemented by SDS-PAGE, analytical SEC, and orthogonal biophysical methods. Produce SPR-grade and structure-grade material, partnering closely with biophysics and structural biology colleagues to ensure reagents meet the demands of binding studies, crystallography, and cryo-EM. Troubleshoot expression and purification of difficult constructs - low-yield, aggregation-prone, chaperone-dependent, or compositionally complex assemblies - and iterate on construct design and conditions to improve behavior. Develop, document, and transfer robust, reproducible protocols; maintain rigorous records and contribute to a culture of data quality and reagent traceability. Communicate results clearly to a cross-functional discovery team and help prioritize a pipeline of targets against project timelines. Who You Are Ph.D. in biochemistry, structural biology, molecular biology, or a related field , with 3-5 years of relevant industry experience supporting protein purification and characterization. (Equivalent experience at the M.S. level with a strong industry track record will be considered for the Scientist level.) Demonstrated, hands-on expertise purifying intracellular proteins from mammalian and baculovirus/insect cell systems at preparative scale. Antibody experience will not be considered relevant for this position. Deep, independent proficiency on Ä

KTA FPLC

systems and a strong command of multi-step chromatographic purification strategy. Practical experience with

SEC-MALS

(e.g., miniDAWN-class detectors) for molar mass and oligomeric-state determination, and an understanding of its assumptions and limitations. Familiarity with common affinity-tag strategies (e.g., His, Twin-Strep, Protein Select / StrepTactin and IMAC-based capture) and sound judgment about tag selection and its impact on folding, solubility, and yield. A track record of delivering protein reagents that enable downstream SPR and structural biology (crystallography and/or cryo-EM). Strong organizational, documentation, and communication skills, and the ability to manage multiple targets in parallel against project priorities. Preferred Qualifications Experience purifying multi-subunit complexes and reconstituting defined-stoichiometry assemblies. Familiarity with multi-gene/multi-cassette expression toolkits (e.g., MultiBac / biGBac, BacMam) and baculovirus generation, amplification, and titering. Hands-on biophysical and analytical characterization beyond

SEC-MALS

- mass photometry, native MS, DLS, nanoDSF/thermal shift, or intact-mass LC-MS. Direct experience generating crystallography- or cryo-EM-grade samples, including buffer optimization and stability screening. Experience supporting small-molecule discovery (DEL, HTS, fragment, or structure-based campaigns) and working alongside medicinal chemistry, biophysics, and computational colleagues. Comfortable with construct design at CROs and handling communication. The Next Step is Yours If you want your science to be the bedrock of a DEL-enabled discovery engine - and you take real satisfaction in handing a colleague a tube of protein that just works - we'd like to hear from you. Bring your rigor, your problem-solving, and your love of difficult targets, and help us turn proteins into structures and structures into medicines. Who We Are Leash Bio is a Salt Lake City-based biotechnology company unleashing machine learning to solve medicinal chemistry problems. We believe the breakthrough in predicting which small molecules bind which proteins won't come from better algorithms alone - it will come from better data, generated at a scale the field has never had. So we built the engine to produce it: we design our own protein constructs, generate the baculoviruses that encode them, express them in insect cells, purify them with lab automation, and screen them against millions of DNA-encoded compounds - measuring small molecule-protein interactions by the billion. That data trains models built to design novel therapeutics for targets that have long resisted small-molecule approaches. The proteins produced in this role are the literal substrate of that mission: no protein, no measurement; no measurement, no model. If you want your work at the bench to compound into something far larger than any single program, this is the place to do it. Benefits include healthcare, 401K match, stock options, free lunches, and access to some of the best outdoor locations in the country. Salary $100,000 - $160,000 per year