azenosertib (ZN-c3) / Zentalis Pharma - LARVOL DELTA

Targeting WEE1 Kinase for Breast Cancer Therapeutics: An Update. (PubMed, Int J Mol Sci) - "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."

Journal • Review • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CDC25C • CDK1 • CDK2 • GNRP • PKMYT1 • STING

Phase 1 dose escalation results of the WEE1 inhibitor, azenosertib (A), in combination with encorafenib (E) and cetuximab (C) in patients (pts) with previously treated BRAF V600E mutant metastatic colorectal cancer (mCRC). (ASCO 2025) - P1 | "The combination of A+E+C was well tolerated at the MTD and yielded response rates in BRAFi-naïve mCRC pts which exceeded the historical data from the E+C doublet."

Clinical • Combination therapy • Metastases • P1 data • Atrial Fibrillation • Cardiovascular • Colorectal Cancer • Fatigue • Neutropenia • Oncology • Solid Tumor • BRAF • CYP2C19 • CYP3A4

The 12-Ethynylmonocarba-closo-dodecaborate Anion: A Ligand for Metal Alkynide Complexes (M = Li, Na, Ca, Zn). (PubMed, Inorg Chem) - "X-ray crystallography and NMR spectroscopy reveal unique coordination geometries, including a rare chair-shaped Li4C2O2 unit in 2a, multinuclear units in 2b-c, and a hexagonal Zn3C3 unit in 2d. Subsequent nucleophilic reactions with benzophenone afford propargylic alcohols (3) with high efficiency, demonstrating their utility in selective synthetic routes for complex molecular assembly. This work not only highlights the reactivity of alkali and alkaline-earth metals in monocarborane metal acetylides but also offers valuable insights into their structural characteristics and potential applications in advanced materials and catalytic systems."

Journal

INK4A/B as predictive biomarkers for enhanced efficacy of dual WEE1 and PKMYT1 inhibition in CDK4/6 inhibitor-resistant breast cancer (AACR 2025) - "This study aimed to identify predictive biomarkers of response to WEE1/PKMYT1 dual inhibition while maintaining manageable toxicity. Evaluating WEE1 inhibitors (adavosertib or azenosertib) in combination with the PKMYT1 inhibitor (lunresertib) across CDK4/6i-R and TNBC models, including patient-derived xenografts (PDXs) and organoids, demonstrated significant tumor suppression, with the novel dual WEE1/PKMYT1 inhibitor SGR-3515 showing comparable efficacy... Dual inhibition of WEE1 and PKMYT1 presents a compelling therapeutic strategy for CDK4/6i-R breast cancer and TNBC. Elevated baseline levels of INK4A and INK4B are strongly associated with enhanced treatment responses, highlighting their potential as predictive biomarkers for selecting patients likely to benefit from WEE1/PKMYT1 dual inhibition therapy."

Biomarker • Clinical • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA • CDKN2A • CDKN2B • ER • HER-2 • PKMYT1

WEE1 as a therapeutic target in TP53 and ARID1A concurrent mutant colorectal cancers (AACR 2025) - P2 | "Notably, ARID1A knockout sensitizes TP53-mutant, but not TP53-wildtype CRC cell lines, to WEE1 inhibitor MK-1775 or ZN-c3...These studies paralleled a phase 1b/2 clinical trial with SC0191 (a novel WEE1 inhibitor) based combination therapy in a cohort of late-line metastatic CRC patients (NCT06363552)...In conclusion, our research showed that targeting WEE1 is effective in TP53 and ARID1A mutant colorectal cancers. This therapeutic strategy is being tested in a phase 2 study for mCRC patients."

Colorectal Cancer • Oncology • Solid Tumor • ARID1A • TP53 • WEE1

Zentalis Pharmaceuticals Announces First Patient Dosed in DENALI Part 2 Clinical Trial of Azenosertib in Patients with Cyclin E1+ PROC (GlobeNewswire) - "Zentalis Pharmaceuticals, Inc...today announced that the first patient has been dosed in Part 2 of the Phase 2 DENALI clinical trial...of azenosertib in patients with Cyclin E1+ platinum-resistant ovarian cancer (PROC)....The Company expects to disclose topline data from DENALI Part 2 by year end 2026 and if successful, this trial has the potential to support an accelerated approval, subject to FDA review."

P2 data • Platinum resistant • Trial status • Ovarian Cancer

Azenosertib is a potent and selective WEE1 kinase inhibitor with broad antitumor activity across a range of solid tumors (AACR 2025) - P1 | "Early clinical data from heavily pretreated patients with different types of cancer show promising signs of activity. Our findings highlight the potential of WEE1 inhibition as a broad therapeutic strategy, for gynecological cancers and various malignant indications."

Endometrial Cancer • Gynecologic Cancers • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • CDK1

The selective WEE1 inhibitor azenosertib shows synergistic anti-tumor activity with encorafenib + cetuximab in multiple BRAFV600E models (AACR 2025) - "Similarly, treatment of multiple BRAFV600E patient-derived xenograft (PDX, N=3) models of CRC resulted in synergistic triplet TGI (80%, 102%, 103%) and some tumor regression compared against monotherapy azenosertib (43%, 19%, 51%) or the E + C doublet (49%, 65%, 87%). Taken together, our results suggest that the in vitro and in vivo combination of azenosertib with E + C enhances tumor growth inhibition over single agent azenosertib or doublet E + C therapy, and may be an effective treatment option for patients with BRAFV600E mCRC."

Colorectal Cancer • Oncology • Solid Tumor

Optimization of therapeutic index of SGR-3515, a first-in-class Wee1/Myt1 inhibitor through intermittent dosing for monotherapy and combination with chemotherapy in xenograft tumor models (AACR 2025) - P1 | "Furthermore it suppresses the acquired resistance associated with a Wee1 inhibitor (ZNc3). The robust anti-tumor activity of SGR-3515, a first-in-class Wee1/Myt1 inhibitor confirms the synergy of Wee1 and Myt1 co-inhibition. SGR-3515 dosing schedule optimization improves therapeutic index as a monotherapy and in combination with Carboplatin. The preclinical data supported the progression of SGR-3515 to clinical study (NCT06463340)."

Monotherapy • Preclinical • Oncology • Solid Tumor • CDK1 • PKMYT1

Cell-free DNA molecular response predicts clinical efficacy in HGSOC patients treated with azenosertib (AACR 2025) - P1, P1/2, P2 | "Molecular response by cfDNA is an early and reliable surrogate endpoint to measure clinical efficacy in HGSOC studies. Molecular response, duration, and depth were predictive of response or stable disease from azenosertib treatment, supporting its further clinical development."

Cell-free DNA • Clinical • Gynecologic Cancers • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • TP53

Loss of RB1 sensitizes TP53-mutated cancer cells to WEE1 inhibition by azenosertib (AACR 2025) - "In xenograft models, azenosertib demonstrated enhanced tumor growth inhibition (TGI) in models with both TP53 and RB1 loss (NCI-H146 [SCLC]: 90%, MDA-MB-468 [TNBC], 87%) compared to those with TP53 mutation alone (DMS53 [SCLC]: 49%, MDA-MB-231 [TNBC] 50%). Together, our data demonstrates loss of RB1 sensitizes TP53-mutant cancer cells to WEE1 inhibition in multiple models of SCLC and TNBC, suggesting RB1 loss can be used as a predictive marker to identify TP53-mutated patients of these cancers who are likely to benefit from WEE1 inhibition by azenosertib."

Breast Cancer • Eye Cancer • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • Triple Negative Breast Cancer • CASP3 • RB1 • TP53

Targeting WEE1 enhances the antitumor effect of KRAS mutated non-small cell lung cancer harboring TP53 mutations (AACR 2025) - "In patient-derived xenograft (PDX) models established from a patient with KRAS-G12C mutation and primary resistance to sotorasib, the combination of sotorasib and the WEE1 inhibitor, ZN-c3, resulted in near-complete tumor regression. This effect was consistently observed across four in vivo models, highlighting the translational potential of this combination therapy.Our findings highlight WEE1 inhibition as a promising therapeutic strategy for KRAS-mutant NSCLC with TP53 mutations. This approach provides a foundation for future clinical investigations to overcome initial resistance to KRAS-G12C inhibitors and improve outcomes for patients with KRAS-mutant NSCLC."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CASP3 • CASP7 • CHEK2 • KRAS • RAD51 • TP53 • WEE1

DENALI: A Study of Azenosertib (ZN-c3) in Subjects With Platinum-Resistant High-Grade Serous Ovarian, Fallopian Tube or Primary Peritoneal Cancer (clinicaltrials.gov) - P2 | N=170 | Recruiting | Sponsor: 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

Enrollment change • Enrollment open • Platinum resistant • Trial completion date • Trial primary completion date • Fallopian Tube Cancer • Oncology • Peritoneal Cancer

Zentalis Pharmaceuticals Announces Poster Presentation at 2025 ASCO Annual Meeting (GlobeNewswire) - "Zentalis Pharmaceuticals...announced that an abstract has been accepted for poster presentation at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting....The poster will include clinical data as of an April 4, 2025 data cutoff from the Company’s ongoing Phase 1/2 clinical trial evaluating azenosertib in combination with encorafenib and cetuximab in patients with metastatic BRAF V600E mutant colorectal cancer."

P1/2 data • Colorectal Cancer

Azenosertib is a potent and selective WEE1 kinase inhibitor with broad antitumor activity across a range of solid tumors. (PubMed, Mol Cancer Ther) - "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."

Journal • Oncology • Solid Tumor • CDK1

Discovery of WEE1 Kinase Inhibitors with Potent Activity against Patient-Derived, Metastatic Colorectal Cancer Organoids. (PubMed, J Med Chem) - "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..."

Journal • Colorectal Cancer • Oncology • Solid Tumor • PLK1 • TP53

Zentalis Pharmaceuticals Reports Full Year 2024 Financial Results and Operational Updates (GlobeNewswire) - "The Company is continuing to enroll patients in its ZN-c3-002 Phase 1b dose escalation trial of azenosertib in the combination cohort with bevacizumab for the treatment of patients with platinum sensitive ovarian cancer. Additionally, the Company is continuing to enroll patients in its TETON (ZN-c3-004) Phase 2 clinical trial of azenosertib as a monotherapy for the treatment of uterine serous carcinoma and expects to present data from this study in the first half of 2026."

Enrollment status • P2 data • Ovarian Cancer • Uterine Cancer

Zentalis Pharmaceuticals to Present Multiple Posters at the American Association for Cancer Research (AACR) Annual Meeting 2025 (GlobeNewswire) - "One poster demonstrating cell-free DNA molecular response as a potential surrogate endpoint to measure clinical efficacy of azenosertib in patients with high-grade serous ovarian cancer (HGSOC). Three additional posters highlighting the potential for broad therapeutic applications of azenosertib as both a single agent and combination therapy as shown in preclinical models."

Biomarker • Preclinical • High Grade Serous Ovarian Cancer

Azenosertib: "12/34 (35%) BRAFi-naïve patients had confirmed response (2 CR, 10 PR)"; Colorectal cancer (Zentalis Pharma) - Corporate Presentation

P1/2 data • Colorectal Cancer • Oncology

The WEE1 Inhibitor Azenosertib Shows Synergistic Anti-Tumor Effects with Microtubule Inhibitor-Based Antibody Drug Conjugates (ADCs) In Preclinical Models (SGO 2025) - No abstract available

Preclinical • Oncology

The Company will also present preclinical data of azenosertib during a poster presentation at the SGO Annual Meeting. (GlobeNewswire) - "The poster data highlights synergistic effects and significantly improved tumor growth inhibition in in vitro and in vivo preclinical models using a combination of azenosertib and microtubule inhibitor-based ADCs. Together with the previous data that azenosertib synergized with TOPO1 inhibitor based ADCs, these results indicate that azenosertib could be used as a generalizable combination partner with ADCs for improving responses in patients with advanced solid tumors."

Preclinical • Solid Tumor

Zentalis Pharmaceuticals Presents Updated Clinical Data at the Society of Gynecologic Oncology 2025 Annual Meeting on Women’s Cancer (GlobeNewswire) - P2 | N=102 | DENALI (NCT05128825) | "Azenosertib median duration of response (mDOR) updated to 6.3 months in the ongoing DENALI Part 1b clinical trial in patients with platinum-resistant ovarian cancer (PROC) and continues to demonstrate an objective response rate (ORR) of ~35% in response-evaluable patients; On track to initiate Part 2 of the ongoing DENALI clinical trial in 1H 2025, with registration-intent topline data anticipated by year end 2026."

P2 data • Trial status • Ovarian Cancer

Cyclin E1 is a Predictive Biomarker of Azenosertib Benefit in Platinum-Resistant Ovarian Cancer (PROC): Outcomes from Part 1b of the DENALI Study (GOG-3066) (SGO 2025) - No abstract available

Biomarker • Oncology • Ovarian Cancer • Solid Tumor • CCNE1

Testing the Combination of the Anticancer Drugs Trastuzumab Deruxtecan (DS-8201a) and Azenosertib (ZN-c3) in Patients With Stomach or Other Solid Tumors (clinicaltrials.gov) - P1 | N=48 | Recruiting | Sponsor: National Cancer Institute (NCI) | Initiation date: Jul 2025 ➔ Feb 2025

Trial initiation date • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Oncology • Solid Tumor

Azenosertib in Uterine Serous Carcinoma: Biomarker Study (clinicaltrials.gov) - P2 | N=25 | Recruiting | Sponsor: Joyce Liu, MD | Not yet recruiting ➔ Recruiting

Biomarker • Enrollment open • Endometrial Serous Adenocarcinoma • Oncology • Solid Tumor • Uterine Cancer