Senior Director, RNAi Discovery

At Pliant, we believe differentiated science can make a meaningful impact. We see our success as a direct result of the central role that each team member plays in advancing our mission to develop therapies that target the disease at its source. We are seeking creative, curious and collaborative individuals who dare to succeed , are committed to making an important impact on patient’s lives and will help us build one Pliant !

Description

We are seeking a Head of RNAi Discovery to build and lead our siRNA discovery engine. This leader will own the end-to-end discovery strategy, from bioinformatic design of siRNA libraries and off-target assessment, through chemistry optimization of hits and in vitro screening, to scale-up of lead assets for in vivo evaluation in mice and non-human primates (NHP) and hand-off of the technical knowledge needed for CMC production.

This is a hands-on scientific leadership role with a primary emphasis on RNAi design and on leading the in vitro screening organization, including cell line selection, assay development and the hit and lead identification cascade. The successful candidate will recruit and develop the team needed to execute, partner closely with biology, DMPK, CMC and program teams, and be accountable for delivering high-quality siRNA development candidates.

This is a hybrid position, requiring 3 days/week at Pliant (South San Francisco).

Responsibilities

- Define and execute the siRNA discovery strategy from target nomination through development candidate selection, including screening cascade design, decision criteria and timelines.

- Lead the bioinformatic design of siRNA libraries, including sequence selection rules, transcript and isoform coverage, cross-species reactivity (human, NHP, mouse), SNP and polymorphism handling, and avoidance of immunostimulatory and other undesirable motifs.

- Direct genome- and transcriptome-wide off-target analysis (seed-mediated and near-match liabilities) to prioritize sequences, and refine the design algorithms and in-house tools as experimental data accumulate.

- Manage the team, and any external vendors, responsible for generating siRNA libraries, ensuring quality, throughput and timely delivery of material for screening.

- Lead chemistry optimization of hits, including modification patterns, thermodynamic asymmetry, seed-region and stabilization strategies, and conjugate attachment, in order to improve potency, duration, specificity and safety.

- Build and lead the in vitro screening team, including selection and qualification of cell lines (endogenous and engineered), assay development and optimization, and validation of assay robustness for hit and lead identification.

- Establish and run the hit-to-lead cascade, including primary screens, dose-response and potency (IC50) determination, selectivity, off-target assessment, stability and early developability readouts.

- Scale up lead siRNAs and coordinate with in vivo pharmacology and DMPK colleagues to design, execute and interpret PK/PD studies in mice and NHP, integrating the results into sequence and chemistry decisions.

- Provide technical knowledge to CMC and external manufacturing partners to bridge discovery and production, including scalability of sequence and chemistry, 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 well documented and reproducible.

- Partner cross-functionally 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 for opportunities to strengthen the platform.

Qualifications

To perform this job successfully, an individual must be able to perform each essential duty. The requirements listed below are representative of the knowledge, skill, abilities, and prior experience required.

- PhD in molecular biology, biochemistry, chemistry, computational biology or a related field, with 12+ years of relevant industry experience, including at least 5+ year experience in RNAi or oligonucleotide therapeutics discovery.

- Demonstrated 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, assay optimization and running hit and lead identification campaigns.

- Experience with in vivo evaluation of siRNAs in mice and NHP, including study design and interpretation of PK/PD data.

- Working knowledge of oligonucleotide manufacturing and CMC considerations, with the ability to translate discovery decisions into scalable, manufacturable leads.

- 5+ years of experience managing scientific teams, with a proven ability to recruit, develop and retain talent and to manage vendors and budgets.

- Strong data analysis skills; proficiency with computational tools and scripting (e.g., Python or R) or the ability to lead those who are.

- Excellent communication and collaboration skills, with the 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.

- Preferred: experience building a discovery platform or team from the ground up.

The annual base salary for this role is $290K – $320K. Individual pay may vary based on additional factors, including, and without limitation job-related skills, experience, work location and relevant education or training. Pliant’s compensation package also includes benefits, equity, and annual target bonus for fulltime positions.

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