Azenosertib

Overview

Azenosertib (also known as ZN‑c3; KP‑2638) is an oral, selective inhibitor of WEE1 kinase in clinical development by Zentalis Pharmaceuticals for solid tumors, with a focus on gynecologic cancers. Early‑ to mid‑stage trials have reported antitumor activity as monotherapy in platinum‑resistant ovarian cancer (PROC) and in small cohorts of uterine serous carcinoma (USC); combination strategies with chemotherapy and targeted agents are also being explored. (ir.zentalis.com)

Mechanism of action

WEE1 is a key regulator of the G1‑S and G2‑M checkpoints via inhibitory phosphorylation of CDK1/2. Inhibition of WEE1 forces cell‑cycle progression despite DNA damage, increasing replication stress and precipitating mitotic catastrophe and apoptosis. Peer‑reviewed preclinical work with azenosertib shows on‑target pharmacodynamics (reduced pY15‑CDK1, increased DNA‑damage markers), robust antitumor activity across xenograft models, and optimized intermittent dosing schedules. Additional studies show synergistic activity with KRASG12C inhibitors in preclinical models. (aacrjournals.org)

Efficacy

• Platinum‑resistant ovarian cancer (monotherapy)

• DENALI phase 2 (Part 1b, single‑arm; 400 mg QD, 5 days on/2 days off): In patients with Cyclin E1–positive PROC, the overall response rate (ORR) was 34.9% among response‑evaluable patients (n=43), with an ORR of 31.3% in the intention‑to‑treat Cyclin E1–positive population (n=48). Median duration of response (mDOR) was reported as approximately 5.5 months at a December 2, 2024 cutoff and 6.3 months at a January 13, 2025 cutoff. In all treated patients (irrespective of biomarker; n≈102), an updated analysis reported ORR 18.6% (ITT) and 20.4% (response‑evaluable). Part 2 (registration‑intent) opened in April 2025. (ir.zentalis.com)

• Uterine serous carcinoma (monotherapy)

• Early data from the phase 1 ZN‑c3‑001 study presented at AACR 2022 reported ORR 27.3% (3/11; 1 unconfirmed CR, 2 confirmed PRs) and disease control rate 90.9% in a small USC cohort; a dedicated phase 2 study in recurrent/persistent USC is ongoing. (cancernetwork.com)

• Combinations

• An ASCO 2023 abstract reported safety run‑in data for azenosertib combined with standard chemotherapies (paclitaxel, carboplatin, gemcitabine, pegylated liposomal doxorubicin) in platinum‑resistant/refractory ovarian cancer; the aim was RP2D determination and biomarker correlation (Cyclin E1). (ascopubs.org)

Peer‑reviewed monotherapy efficacy publications in humans remain limited; most clinical efficacy data to date come from conference presentations and company‑sponsored updates.

Safety

• Class‑consistent adverse events are primarily hematologic (neutropenia, thrombocytopenia, anemia) and gastrointestinal (nausea, diarrhea, vomiting), with fatigue also common. In combination cohorts with chemotherapy, grade ≥3 hematologic toxicities were frequent, as expected. Intermittent monotherapy dosing (e.g., 5 days on/2 days off) is used to improve tolerability. (trial.medpath.com)
• In June 2024, the FDA placed a partial clinical hold on several azenosertib studies after two treatment‑related deaths from presumed bloodstream infection in an ovarian cancer trial; the hold was lifted in September 2024 following the company’s safety assessment and mitigation steps, and enrollment resumed. (reuters.com)
• Company summaries from dose‑finding studies (ZN‑c3‑001 and MAMMOTH) describe low rates of grade ≥3 gastrointestinal events and manageable hematologic toxicity with intermittent monotherapy dosing; rare treatment‑related grade 5 events have been reported. Detailed peer‑reviewed monotherapy safety datasets are pending. (biospace.com)

Ongoing and planned studies (selected)

• DENALI (NCT05128825): Phase 2, PROC; Part 2 (registration‑intent) initiated April 2025. (ir.zentalis.com)
• Phase 2 USC monotherapy (NCT04814108): recurrent/persistent USC; multicenter. A separate biomarker‑rich phase 2 USC study (NCT06369155) is also active. (clinicaltrials.ucsf.edu)
• Combination studies with chemotherapy in ovarian cancer (e.g., NCT04516447 safety run‑in). (ascopubs.org)

Further reading

• Peer‑reviewed preclinical characterization of azenosertib’s selectivity, PD, and antitumor activity. (aacrjournals.org)
• Preclinical synergy with KRASG12C inhibitors. (aacrjournals.org)
• ASCO 2023 abstract on azenosertib plus chemotherapy in ovarian cancer (biomarker correlations). (ascopubs.org)
• Conference and company updates summarizing DENALI Part 1b monotherapy results in PROC (response rates, mDOR) and Part 2 initiation. (onclive.com)
• USC: early phase data and ongoing trials. (cancernetwork.com)
• Regulatory/safety updates regarding the 2024 partial clinical hold and its resolution. (reuters.com)

Notes - KP‑2638 is listed as an alternate name in multiple clinical‑trial registries; most peer‑reviewed and conference materials refer to the molecule as azenosertib or ZN‑c3. (clinicaltrials.ucsf.edu)

Last updated: Oct 2025