azenosertib (ZN-c3)

P1, N=44, Terminated, K-Group, Beta, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc | Trial completion date: Sep 2026 --> Jul 2025 | Active, not recruiting --> Terminated; Study terminated due to change in therapeutic landscape.

Adavosertib's clinical promise was challenged by inter-individual variations in response and side effects. Because of these promising preclinical outcomes, other WEE1 kinase inhibitors (Azenosertib, SC0191, IMP7068, PD0407824, PD0166285, WEE1-IN-5, Zedoresertib, WEE1-IN-8, and ATRN-1051) are being developed, with several currently being evaluated in clinical trials or as an adjuvant to chemotherapies...Reliable predictors of clinical responses based on mechanistic insights remain an important unmet need. Herein, we review the role of WEE1 inhibition therapy in breast cancer.

P2, N=170, Recruiting, K-Group, Beta, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc | Active, not recruiting --> Recruiting | N=102 --> 170 | Trial completion date: Oct 2025 --> Jun 2027 | Trial primary completion date: Apr 2025 --> Dec 2026

Phase I studies with azenosertib as monotherapy have shown preliminary clinical activity in patients with advanced solid tumors. The data presented herein supports further studies of azenosertib monotherapy across multiple solid tumor indications.

A library of potent WEE1 kinase inhibitors was synthesized based on the discontinued frontrunner clinical candidate AZD1775 (1), many of which were more selective for WEE1 over an undesirable off-target of 1, the kinase PLK1. When tested against patient-derived organoids (PDOs) grown from TP53-mutated colorectal cancer (CRC) peritoneal metastases, 34 (IC50 value of 62 nM) exhibited stronger efficacy than 1 (IC50 value of 120 nM) and the best-in-class clinical candidate ZN-c3 (IC50 value of 127 nM). Against primary CRC PDOs with TP53-WT, 34 significantly enhanced DNA damage, replication stress and apoptosis compared to 1, as well as demonstrated high selectivity over patient-matched normal healthy colon PDOs, highlighting a potential therapeutic window for cancer treatment. Overall, this investigation provides critical insight into several potent WEE1 inhibitors that exhibited exceptional efficacy against CRC PDOs and is the first to utilize a PDO platform to assess their effect on healthy and malignant cell viability.

Our findings show that combined inhibition of RNR and WEE1 was effective against Ewing's sarcoma in vitro. They thus provide a rationale for the evaluation of the potential of combined targeting of RNR and WEE1 in Ewing's sarcoma in vivo.

P1, N=44, Active, not recruiting, K-Group, Beta, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc | Phase classification: P1/2 --> P1 | N=82 --> 44 | Trial primary completion date: Aug 2026 --> Jul 2024

Finally, analysis of biomarkers from in vitro and in vivo tumor samples displayed increases in protein markers of RS, DNA damage, and apoptosis after combination treatment. Taken together, our results suggest that the combination of azenosertib with KRASG12C inhibitors enhances tumor growth inhibition over single agent therapy and may be an effective treatment strategy for patients with KRASG12C tumors.

P1/2, N=78, Recruiting, Filipa Lynce, MD | Suspended --> Recruiting

P1/2, N=82, Active, not recruiting, K-Group, Beta, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc | Recruiting --> Active, not recruiting

P2, N=76, Recruiting, K-Group, Beta, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc | Active, not recruiting --> Recruiting

P1/2, N=40, Terminated, K-Group Alpha, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc. | N=95 --> 40 | Trial completion date: Feb 2026 --> Jul 2024 | Recruiting --> Terminated | Trial primary completion date: Mar 2025 --> Jul 2024; Sponsor decision