Senior Director, RNAi Discovery

Pliant Therapeutics, Inc.•South San Francisco, CA

5d•$290,000 - $320,000•Hybrid

About The Position

Pliant is seeking a Head of RNAi Discovery to build and lead its siRNA discovery engine. The role owns the end-to-end discovery strategy, from bioinformatic design of siRNA libraries and off-target assessment through chemistry optimization, in vitro screening, and scale-up of lead assets for in vivo evaluation in mice and non-human primates (NHP), as well as transfer of technical knowledge for CMC production. This is a hands-on scientific leadership position focused on RNAi design and leadership of the in vitro screening organization, including cell-line selection, assay development, and hit and lead identification. The successful candidate will recruit and develop a team, partner closely with biology, DMPK, CMC, and program teams, and be accountable for delivering high-quality siRNA development candidates. The position is hybrid and requires three days per week at Pliant in South San Francisco.

Requirements

PhD in molecular biology, biochemistry, chemistry, computational biology, or a related field.
12+ years of relevant industry experience, including at least 5+ years in RNAi or oligonucleotide therapeutics discovery.
Track record of advancing siRNA programs from design through lead optimization and in vivo proof of concept, ideally to a development candidate or IND.
Deep expertise in siRNA design, including bioinformatic library design and genome- and transcriptome-wide off-target analysis.
Strong understanding of siRNA chemistry and structure-activity relationships, including modification patterns and conjugation strategies, and experience optimizing hits for potency, durability, and safety.
Hands-on experience in in vitro screening, including cell-line selection, assay development and optimization, and hit and lead identification campaigns.
Experience evaluating siRNAs in mice and NHP, including study design and interpretation of PK/PD data.
Working knowledge of oligonucleotide manufacturing and CMC considerations, with ability to translate discovery decisions into scalable, manufacturable leads.
5+ years of experience managing scientific teams, including recruiting, developing, and retaining talent, and managing vendors and budgets.
Strong data analysis skills and proficiency with computational tools and scripting such as Python or R, or the ability to lead those who are.
Excellent communication and collaboration skills, including ability to influence cross-functional teams and present to senior leadership.
Record of scientific impact, such as publications and patents in RNAi or oligonucleotide therapeutics.

Nice To Haves

Experience building a discovery platform or team from the ground up.

Responsibilities

Define and execute the siRNA discovery strategy from target nomination through development candidate selection, including screening cascade design, decision criteria, and timelines.
Lead bioinformatic design of siRNA libraries, including sequence selection rules, transcript and isoform coverage, cross-species reactivity, SNP and polymorphism handling, and avoidance of undesirable motifs.
Direct genome- and transcriptome-wide off-target analysis and refine design algorithms and in-house tools as experimental data accumulate.
Manage the team and external vendors responsible for generating siRNA libraries, ensuring quality, throughput, and timely delivery.
Lead chemistry optimization of hits to improve potency, duration, specificity, and safety.
Build and lead the in vitro screening team, including cell-line selection and qualification, assay development and optimization, and validation of assay robustness.
Establish and run the hit-to-lead cascade, including primary screens, dose-response and potency determination, selectivity, off-target assessment, stability, and early developability readouts.
Scale up lead siRNAs and coordinate with in vivo pharmacology and DMPK colleagues on PK/PD studies in mice and NHP, integrating results into sequence and chemistry decisions.
Provide technical knowledge to CMC and external manufacturing partners to bridge discovery and production, including scalability, impurity profile, analytical characterization, and process considerations.
Apply rigorous data analysis, statistics, and computational or machine learning approaches to guide design and prioritization, and ensure data are documented and reproducible.
Partner with biology, translational, toxicology, DMPK, CMC, regulatory, and program teams, and represent siRNA discovery in project teams and governance reviews.
Contribute to intellectual property strategy, patent filings, publications, and scientific presentations, and monitor the external RNAi landscape and emerging technologies.