2026
Small-Molecule Modulators of HIPK4 Activity and Proteostasis ↗
Chemical tools for investigating HIPK4 activity and protein handling across cell types.
Zaile (Felix) Zhuang is a medicinal chemist and chemical biologist at Stanford University.
He designs small molecules to understand protein function and advance drug discovery. His current research focuses on non-hormonal male contraception.
Interested in drug discovery across therapeutic areas.
01 / AboutZaile (Felix) Zhuang, PhD
Following a question.
One molecule at a time.
My work connects organic and medicinal chemistry, chemical biology, and drug discovery. I’m a postdoctoral scholar in James K. Chen’s laboratory in Stanford’s Department of Chemical and Systems Biology.
I studied chemistry at the University of Waterloo, then completed my PhD at the University of British Columbia. My doctoral research used the chemistry of enzyme reactions to design inhibitors, including molecules that act on enzymes responsible for tubulin polyglycylation.
At Stanford, my current focus is HIPK4 and its potential as a target for non-hormonal male contraception. Across my doctoral and postdoctoral research, I connect molecular design and synthesis with biochemical and cellular experiments. I’m interested in applying this approach to new targets and therapeutic areas.
02 / ResearchDesign → test → understand
Small molecules.
Biological insight.
My research connects molecular design and synthesis with biochemical and cellular experiments. I investigate how a molecule’s structure affects activity, selectivity, and protein regulation, using those relationships to guide the next round of chemistry.
DesignDesign, synthesize, and refine small molecules.
MeasureTest activity, selectivity, and behavior in cells.
UnderstandConnect molecular structure to mechanism and biological effects.
Current focus / HIPK4 & male contraception
HIPK4 is a kinase involved in sperm development. Earlier research showed that male mice lacking the Hipk4 gene are infertile. That observation creates a starting point for chemistry: can small molecules help us understand—and eventually control—this protein’s function? [1]
Our work identified HIPK4 inhibitors and a further finding: some ligands also alter how cells handle the protein. The effects depend on the cell type—degradation in HEK293T cells, and aggregation in spermatids, the cells developing into sperm. [2]
Discovery-stage research. These chemical tools do not yet establish contraceptive efficacy, safety, or reversibility in people.
03 / Contraception historySelected milestones / 1855–2025
A long history.
An unfinished story.
From barriers and permanent contraception to hormonal approaches and molecular targets. Progress has brought new possibilities—and new questions about safety, reversibility, and everyday use.
- 1855
Rubber changes the condom.
The first rubber condom was produced in 1855. Later advances in latex manufacturing made condoms thinner, stronger, and easier to manufacture, helping establish a barrier method that remains central to male contraception.
Dittrick Medical History Center ↗ - 1974
A less invasive approach to vasectomy.
The no-scalpel technique was developed in China, changing how clinicians access the vas deferens. It refined an established procedure; vasectomy is still intended as permanent contraception.
Li et al. · Journal of Urology, 1991 ↗ - 1990
Hormonal contraception demonstrates its potential.
A WHO trial showed that testosterone could provide effective contraception in men whose sperm production was sufficiently suppressed. The results established clinical proof of concept, while variable suppression and weekly injections left practical challenges.
WHO Task Force · The Lancet, 1990 ↗ - 2016
Efficacy meets the challenge of tolerability.
Published results from a testosterone–progestogen injection study showed effective sperm suppression and pregnancy prevention. Injections had been stopped early after a safety review, with mood-related and other adverse events underscoring the importance of tolerability.
Behre et al. · JCEM, 2016 ↗ - 2023
An on-demand concept works in mice.
Inhibiting soluble adenylyl cyclase temporarily prevented pregnancies in mice, with fertility returning the following day. The study supported a new approach to sperm function; human contraceptive safety and efficacy remained to be tested.
Balbach et al. · Nature Communications, 2023 ↗ - 2025
A non-hormonal pill reports early human results.
A Phase 1a study found single doses of YCT-529 generally well tolerated in 16 vasectomized men. This was an early safety and pharmacokinetic milestone—not a test of pregnancy prevention.
Mannowetz et al. · Communications Medicine, 2025 ↗
Dates mark selected introductions or published findings. This is a brief timeline, rather than a complete history of the field.
04 / Contraception researchResearch snapshot / 22 Oct 2026
More than one
way forward.
Several approaches are being explored in parallel. Some have reached human studies; others are still defining what a promising target can do.
Select a project to read more ↓
Showing 5 approaches.
NES/T gelHormonal suppressionPhase 2b complete
Phase 3 planned
A daily skin gel combining segesterone acetate and testosterone, designed to suppress sperm production while maintaining circulating testosterone. The sponsor reports completion of a Phase 2b study and planning for Phase 3. The product remains investigational.
Population Council · February 2026 ↗Program update ↗YCT-529Retinoid signaling / oral candidateEarly clinical research
Phase 1b/2a program
YCT-529 targets retinoic acid receptor alpha, part of the vitamin A signaling pathway involved in sperm production. Following an initial single-dose human study, it entered a repeat-dose Phase 1b/2a program. Human pregnancy prevention has yet to be established.
Trial registry · NCT06542237 ↗Initial human study ↗ADAM hydrogelPhysical blockage of sperm transportFirst human study complete
Phase 2 planned
A hydrogel placed inside the vas deferens to block sperm transport without relying on hormones. The sponsor reports completion of its first human study and preparation for Phase 2. Long-term performance and reliable reversal require continued clinical evaluation.
Sponsor’s clinical pipeline ↗About the approach ↗sAC inhibitorsSperm function / on-demand conceptPreclinical research
Evidence in animal models
This approach targets soluble adenylyl cyclase, an enzyme needed for sperm movement and fertilization. A short-acting inhibitor temporarily prevented pregnancies in mice in a 2023 study. Researchers are developing compounds for further testing toward human studies.
Primary mouse study ↗Development update · MCI ↗HIPK4Sperm development / my researchDiscovery-stage research
Chemical probes & cellular biology
Chemical probes help investigate a kinase needed for normal sperm development in mice. My work studies HIPK4 inhibition and how ligands change protein handling in cells. These experiments provide tools and evidence for exploring a potential contraceptive target.
Our published study ↗More about my research ↓Stages reflect the latest sources reviewed on 22 October 2026. Planned trials are not completed trials. Each approach still has to establish the evidence required for its intended use.
05 / Selected work2022–2026
The papers.
2026
Macrocyclization of Broad-Spectrum Kinase Inhibitor Bosutinib Leads to Potent and Selective Quinoline-Based HIPK4 Inhibitor AZ137 ↗
Collaborative medicinal chemistry to develop a selective probe of HIPK4 function.
2022
Phosphinic acid-based inhibitors of tubulin polyglycylation ↗
Mechanism-inspired inhibitors for studying enzymes that add glycine chains to tubulin.
2022
A guanidinium group is an effective mimic of the tertiary carbocation formed by isopentenyl diphosphate isomerase ↗
Using an enzyme’s reaction chemistry to guide inhibitor design.
06 / ContactStanford, California
Let’s talk.
I welcome conversations about research opportunities and collaborations in medicinal chemistry, chemical biology, and small-molecule drug discovery across therapeutic areas.
zailez@stanford.edu ↗