azenosertib (ZN-c3)

P2, N=25, Not yet recruiting, Joyce Liu, MD

P1, N=48, Not yet recruiting, National Cancer Institute (NCI)

P1/2, N=78, Not yet recruiting, Filipa Lynce, MD

P2, N=34, Recruiting, Brandon Huffman | Not yet recruiting --> Recruiting

P2, N=130, Recruiting, K-Group, Beta, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc | Trial completion date: Dec 2023 --> May 2025 | Trial primary completion date: Dec 2022 --> Nov 2024

P1/2, N=84, Active, not recruiting, K-Group, Beta, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc | Recruiting --> Active, not recruiting

P1, N=43, Not yet recruiting, The Netherlands Cancer Institute

P1, N=0, Withdrawn, OHSU Knight Cancer Institute | N=14 --> 0 | Not yet recruiting --> Withdrawn

This open-label, multicenter study (NCT04516447) assessed azenosertib + paclitaxel (PAC), carboplatin (Carbo), gemcitabine (GEM), or pegylated liposomal doxorubicin (PLD) in pts with metastatic high-grade serous EOC after ≤2 lines of CT including platinum CT. Azenosertib + CT is well tolerated and has encouraging clinical activity, with durable responses in pts with platinum R/R EOC. Pts with Cyclin E1 overexpressing tumors, a subgroup with suboptimal benefits from CT, demonstrated significant improvements in ORR and PFS vs pts with tumors having low expression. These data support a planned trial of azenosertib + CT vs CT alone in Cyclin E1 overexpressing platinum R/R EOC.

This report summarizes encouraging clinical development of WEE1i in gynecological cancers and considers its application in future studies. Biomarker-driven patient selection might be essential to increase the response rates.

Importantly, ATRN-W1051 exhibits low off-target inhibition of the PLK family of kinases (PLK1, PLK2 and PLK3), which are substantially inhibited by the leading WEE1i in the clinic (AZD1775 and ZN-c3)1. These preclinical data suggest that ATRN-W1051 may be a potential therapeutic candidate for CCNE1-overexpressing HGSOC. Together, ATRN-119 and ATRN-W1051 provide promising alternative DNA replication checkpoint inhibitors for the treatment of a variety of cancers.

Overall, ZN-c3 is well tolerated, achieves pharmacologically-relevant unbound concentrations in GBM PDX models, and is associated with significant checkpoint modulation. Preclinical evaluation of ZN-c3 in combination with radiation therapy and DNA damage response pathway inhibitors is currently underway, which will support future combinatorial strategy for glioblastoma treatment.

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

P1/2, N=82, Not yet recruiting, K-Group, Beta, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc

P1, N=14, Not yet recruiting, OHSU Knight Cancer Institute | Initiation date: Dec 2022 --> Jul 2023

P1/2, N=95, Recruiting, K-Group Alpha, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc.

P1, N=0, Withdrawn, M.D. Anderson Cancer Center | N=74 --> 0 | Trial completion date: Mar 2025 --> Dec 2022 | Not yet recruiting --> Withdrawn | Trial primary completion date: Mar 2025 --> Dec 2022

P1, N=14, Not yet recruiting, OHSU Knight Cancer Institute | Initiation date: Aug 2022 --> Dec 2022

P1, N=74, Not yet recruiting, M.D. Anderson Cancer Center

P1, N=14, Not yet recruiting, OHSU Knight Cancer Institute

"Zentalis Pharmaceuticals, Inc....announced a strategic collaboration with Caris Life Sciences, the leading molecular science and technology company actively developing and delivering innovative solutions to revolutionize healthcare. Through this partnership, Caris will sequence individuals’ complete exome and transcriptome, leverage real-world data to help inform clinical development and help identify eligible patients for Zentalis’ clinical trials. Initially, Caris will assist in the recruiting efforts for Zentalis’ clinical trials investigating the Wee1 inhibitor, ZN-c3....Under the terms of the agreement, Zentalis retains full ownership of its therapeutic candidates."

Small molecule WEE1 inhibitors, such as AZD1775 and Zn-C3, are currently being evaluated in the clinic and have demonstrated promising efficacy in solid tumors including ovarian, colon, and uterine carcinoma.By applying Schrödinger’s computational platform including Free Energy Perturbation (FEP) and Protein FEP, we have identified novel, potent, and highly selective WEE1 inhibitors with IC50 values in the low nanomolar range in a biochemical kinase activity assay and cellular target engagement (CDK1 pTyr15) IC50s of 100 - 300 nM in A427 and OVCAR3 cell lines. In summary, we have identified novel, potent and exquisitely selective WEE1 kinase inhibitors that demonstrate robust anti-tumor activity and sustained target engagement in tumor models. The compound’s anti-tumor effects are maintained with dosing holidays while allowing full recovery of mechanism-based hematological effects.

These results justify testing the ZN-d5 and ZN-c3 combination or possibly the triple combination including azacitidine in AML patients independently of TP53 status. Due to synergism observed with these combination(s) and activity in samples from patients resistant to venetoclax, activity may be seen in patients with low sensitivity to Bcl-2 inhibitors or even in patients who progressed on venetoclax plus azacitidine.

In the ER-positive MCF-7 efficacy model, ZN-c3 demonstrated anti-tumor activity as a single agent as well as in combinations with a CDK4/6 inhibitor (Palbociclib) or ZN-c5, a selective estrogen receptor degrader (SERD). In the MDA-MB-436, a triple negative breast cancer tumor xenograftmodel, ZN-c3 demonstrated efficacy as a single agent and in combination with the PARP inhibitors Olaparib or Niraparib...Moreover, ZN-c3 can overcome the acquired resistance to PARP inhibitors and trastuzumab. ZN-c3 is currently in clinical trials for several indications and has demonstrated promising clinical activity and good tolerability.

P1/2, N=138, Recruiting, K-Group Beta | Not yet recruiting --> Recruiting

P1/2, N=138, Not yet recruiting, K-Group Beta