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Next-generation investigational Wee1 and ATM inhibitors' initial data is on cell cycle disruption and double-strand break repair 2,3,5,6 LONDON, UK I April 18, 2016 I AstraZeneca today announced new data from multiple molecules in its industry-leading DNA Damage Response (DDR) pipeline at the 2016 American Association for Cancer Research .

Adavosertib (MK-1775, AZD1775) is a potent and selective Wee1 inhibitor with IC50 of 5.2 nM in a cell-free assay; hinders G2 DNA damage checkpoint. Guertin A et al.

Researchers at ASCO shared data pointing to gene amplification, protein overexpression, and TP53 mutations as biomarkers for identifying best responders to adavosertib. SIGNIFICANCE: ATR and WEE1 inhibitors demonstrate effective antitumor activity in preclinical models of DLBCL associated with replication stress, but new mechanistic insights and biomarkers of response support a differentiated clinical development strategy.

CHICAGO - AstraZeneca's investigational WEE1 inhibitor adavosertib showed potential in biomarker-selected advanced ovarian cancer populations in two studies presented during the American Society of Clinical Oncology's annual meeting Saturday. Wee1 Inhibitor Gets Win in Tough-to-Treat Ovarian Cancer . PD0166285, a ppyrido [2,3-d] pyimidine compound, being developped by Pfizer [4] Additionally, PAXIP1 was found to be elevated in 12% of ovarian cancers. However, it has been shown that AZD1775 have a binding affinity to plk1 kinase and jak2, 3, and some other kinases [, , ]. Like PARP inhibitors, the inhibition of WEE1 is focused on the DDR pathway. AstraZeneca rolled out early data on its PARP1-selective, next-gen inhibitor AZD5305 at the virtual AACR meeting Saturday, hoping to highlight the drug's chances at following up and . The Wee1 inhibitor, adavosertib, has demonstrated activity alone and in combination with olaparib in PARP inhibitor (PARPi)-resistant preclinical models.

Inhibition of WEE1 can induce mitotic catastrophe and apoptosis.1 ZN-c3 is a novel selective inhibitor of WEE1 (Figure 1).2 Figure 1. by Ian Ingram, Deputy Managing Editor, MedPage Today January 25, 2021 Adding the Wee1 inhibitor adavosertib to gemcitabine reduced the risk of disease progression and death in women with recurrent,. Abstract. selective cytotoxicity of ATM, ATR or Wee1 blockade either alone or in combination with PARP inhibitor in XRCC1 deficient cancers. . This is admittedly a short list, with Zentalis having most at stake: the Wee1 inhibitor ZN-c3 is the company's lead project. Phase 2. AstraZeneca is also developing a WEE1 inhibitor, adavosertib, but its safety, tolerability and "awkward" dosing regimen could be its "Achilles heel," SVB Leerink analyst Andrew Berens, M.D., wrote in an investor note Thursday evening, noting that adavosertib led to anemia in 52% of patients, low platelet counts in 48% of patients and .

Preclinical Evaluation of the WEE1 Inhibitor MK-1775 as Single-Agent Anticancer Therapy. A Phase 2 Study of the Wee1 Inhibitor AZD1775 in Women With Recurrent or Persistent Uterine Serous Carcinoma or Uterine Carcinosarcoma: Actual Study Start Date : October 22, 2018: . DelveInsight's, "WEE1 protein inhibitors - Pipeline Insight, 2022" report provides comprehensive insights about 5+ companies and 5+ pipeline drugs in WEE1 protein inhibitors pipeline landscape.

Adavosertib (also known as AZD 1775, MK 1775) is a small-molecule inhibitor of the tyrosine kinase WEE1 that is being developed by AstraZeneca for the treatment Adavosertib - AstraZeneca .

AstraZeneca (AZ) has unveiled early data for its next-generation PARP1 selective inhibitor AZD5305 - a potential successor to its blockbuster PARP treatment Lynparza. . selective oestrogen receptor degrader + CDK4/6 inhibitors 1st-line HR+ HER2- breast cancer . . . A review of a third generation of novel DDR targets . 5505 Background: Wee1 phosphorylates and inhibits cyclin-dependent kinases 1 and 2 and is involved in regulation of the intra-S and G2/M cell cycle checkpoint arrest for premitotic DNA repair. . Other WEE1 inhibitors include: Adavosertib, also known as AZD1775 or MK-1775, a small-molecule, pyrazolpyrimidine derivative and potent and ATP-competitive specific inhibitor of the WEE1 kinase, being developed by AstraZeneca. AZD1775 is a drug that has been shown to increase the effect of cisplatin and of radiotherapy when tested in the laboratory. AstraZeneca Annual Report & Form 20-F Information 2017 / Additional Information 201 Additional Information can . PURPOSE Outcomes in RAS-mutant metastatic colorectal cancer (mCRC) remain poor and patients have limited therapeutic options. 12. Its other products are ZN-c3, an inhibitor of WEE1, a protein tyrosine kinase, in Phase 1/2 trial targeting advanced solid tumors; ZN-d5, a selective inhibitor of B-cell lymphoma 2 for the . The firms will use Genomic Vision's FiberVision DNA molecular combing platform to study the effects of AstraZeneca's WEE1 inhibitor on DNA replication progression in cancer cells and further. The market is attractive as evidenced by the WEE1 inhibitor AZD1775 that is involved in 27 clinical trials that are currently recruiting. 2019 American Association for Cancer Research. A landscape overview of the DDR Therapeutic landscape, focusing on the first generation of approved PARP inhibitors. inhibitor), DNA-PK 2016 -2018 2019 -2021 Launch Lynparza combinations (VEGF, IO) 2022 -2025 Expand Lynparzabeyond BRCA(Study 08, prostate . National Institutes of Health. AstraZeneca's unique DDR pipeline will also be illustrated through an oral presentation of Phase I data on the WEE1 inhibitor, AZD1775, in combination with radiation therapy and temozolomide in patients with newly diagnosed glioblastoma multiforme (GBM) and evaluation of intratumoral drug distribution in patients with recurrent GBM (Abstract . Targets Wee1 (Cell-free assay) . A further irony for Astrazeneca is that the study, called Focus4-C and conducted in metastatic colorectal cancer Furthermore, Wee1 inhibition prolongs mitosis in a range of cancer cells and makes them more susceptible to chemotherapy-induced mitotic catastrophe ( 9 ). Wee1 is a kinase controlling G/M and S phase checkpoints via phosphorylation of the cyclin-dependent kinases CDK1 and CDK2.

important for others that have put Wee1 inhibitors into the clinic more recently. Most of the preclinical and clinical studies have been performed using WEE1 inhibitor from AstraZeneca, namely AZD1775 (MK1775 or adavosertib). (ATR, CHK1, and WEE1) inhibitors is being investigated clinically in many cancers, particularly in ovarian cancer, to enhance the efficacy and circumvent resistance to PARPis . 2. Olaparib (AZD2281), ATM inhibitor (AZ31) and ATR inhibitor (AZD6738) were kindly provided by AstraZeneca Pharmaceuticals. AZD1775# + chemotherapy Wee1 inhibitor + chemotherapy ovarian cancer II Q4 2012 AZD1775# Wee1 inhibitor solid tumours II Q1 2016 vistusertib (AZD2014) mTOR inhibitor solid tumours II Q1 2013 . METHODS Patients with newly diagnosed mCRC were registered into . The observed clinical efficacy of a Wee1 inhibitor combined with gemcitabine supports ongoing assessment of DNA damage response drugs in high-grade serous ovarian cancer, a TP53-mutated tumour type with high replication stress. AstraZeneca) is a specific Wee1 kinase inhibitor. WEE1 inhibition can increase genomic instability by inducing replication stress and G2/M checkpoint inactivation, which result in increased cellular sensitivity to DNA damaging agents. The WEE1 inhibitor MK-1775 is designed to cause certain tumour cells to divide without undergoing the normal DNA repair processes . Biomarkers May Identify Ovarian Cancer Patients Who Benefit From AstraZeneca WEE1 Inhibitor. received research funding from AstraZeneca, Bayer, and Karyopharm and honoraria from AstraZeneca, MSD, Tessa Therapeutics, Novartis, Bayer, and Genmab. The challenges ahead are in the establishment of the optimum dosing schedule either alone or in combination and the identification of patients with specific biomarker profiles who benefit most. Abstract Background: Adavosertib is a highly selective inhibitor of Wee1, a crucial regulator of intra-S and G2/M cell cycle checkpoints. A detailed look at the preclinical and clinical second generation DDR assets, including; specialized PARP-targeted assets, ATR, and WEE1 inhibitors. . The Moffitt WEE1 inhibitor might not show toxicity in humans, except maybe in combination regimens, in light of the recent AZD1775 Phase 1 data. Using PAXIP1 as a biomarker . PD-L1+Wee1 solid tumours Imfinzi #+RT (platform) . Layout table for investigator information; Principal Investigator: Joyce Liu, MD: Dana-Farber Cancer Institute: It also covers the therapeutics assessment by product type . Adavosertib (AZD1775) is an orally active, first-in-class, small-molecule reversible inhibitor of WEE1 kinase [].WEE1 is a protein tyrosine kinase that phosphorylates and inhibits cyclin-dependent kinase 1 (CDK1), which drives cells from the G2 phase into mitosis, and CDK2, which drives cells through the S phase of the cell cycle [1, 2].In response to DNA damage, WEE1 inhibits both CDK1, to . The Moffitt WEE1 inhibitor might not show toxicity in humans, except maybe in . In the Phase 1 trial of AZD1775 10% of evaluable patients (17/176 . The 5th Digital DDR, ATR & PARP Inhibitors Summit is coming at a timely inflection point within this field. Beyond Lynparza, AstraZeneca has a number of assets in phase 2 and in early development: a WEE1 inhibitor (adavosertib, AZD1775), an ATR inhibitor (AZD6738), two ATM inhibitors (AZD1390 and AZD0156), and a DNA-PK inhibitor, all of which target different aspects of the DDR, and these could be deployed either in monotherapy, or in combination .

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We considered an increase in genomic instability induced by WEE1 inhibition might be used to augment the effects of drugs targeting DNA repair protein. IMP7068 is a Wee1 inhibitor internally discovered and developed by Impact Therapeutics, with worldwide intellectual property rights. TP53. (AstraZeneca), Ro-3306 and PHA767491 (Selleckchem), and CVT-313 (Santa Cruz).

Zentalis Pharmaceuticals is developing a WEE1 inhibitor that it hopes to combine with PARP inhibitors and other cancer medicines to boost their efficacyand its early phase 1 data are promising.. Knowledge Generated Adavosertib demonstrated clinical activity in USC, with a response rate of 29.4% and with 47.1% of patients remaining progression-free at 6 months. Subsequent experiments revealed that this correlation was not universally true, although Wee1 inhibitor activity is still likely linked to G1/S checkpoint deficiencies in one form or another (11). WEE1 tyrosine kinase is a critical component of the G2/M cell cycle checkpoint that phosphorylates CDK1 (p-CDK1), inducing cell cycle arrest in the presence of DNA damage to allow for DNA repair.

AstraZeneca licensed the Phase 2 drug from Merck in 2013 with a $50M upfront payment, with unspecified royalties and milestones.

We show that WEE1i induces CDK1-dependent RIF1 phosphorylation and CDK2- and CDC7-dependent activation of the replicative helicase. WEE1 inhibition can increase genomic instability by inducing replication stress and G2/M checkpoint inactivation, which result in increased cellular sensitivity to DNA damaging agents. Like PARP inhibitors, the inhibition of WEE1 is focused on the DDR pathway.

The potent WEE1 inhibitor AZD1775 has advanced to clinical trials in combination with DNA-damaging agents such as carboplatin, cisplatin, docetaxel, . ZN-c3 is an oral inhibitor of WEE1 that is aiming to generate sufficient DNA damage in cancer . This compound is currently in Phase IIa clinical trials for patients with p53 deficient ovarian cancers and achieved a 27% response rate.

Responses were durable, with a median duration of response of 9.0 months. Adavosertib - the ADAGIO Phase II multicenter trial of the WEE1 inhibitor adavosertib as a treatment for recurrent or persistent uterine serous carcinoma, a highly aggressive form of endometrial . Features: The first reported Wee1 inhibitor. Methods Highly selective inhibitors of ATR (AZD6738), ATM (AZ31) and Wee1 (AZD1775) either alone or in combination with olaparib were tested for synthetic lethality in XRCC1 deficient TNBC or HeLa . The selective Wee1 inhibitor AZD1775 and the pan-HDAC inhibitor Vorinostat (formerly SAHA) were provided by AstraZeneca (Wilmington, DE, USA) and Merck (Whitehouse Station, NJ, USA) through . Most of the preclinical and clinical studies have been performed using WEE1 inhibitor from AstraZeneca, namely AZD1775 (MK1775 or adavosertib). Cell viability assay Cell viability was measured using MTT assay. AstraZeneca's WEE1 inhibitor, AZD-1775, was licensed from Merck for an upfront payment of $50M. atmosphere. Another highly selective and potent WEE1 inhibitor Debio0123 from Debiopharm is currently being tested with carboplatin in a first-in human phase 1 study (NCT03968653) and the first two dose levels were .

Mol Cancer Ther; 12(8) August 2013: 1442-1452. The biomarker PAXIP1 was identified in screens of lung cancer tumors to be co-expressed with the cell cycle regulator WEE1 in 19-30% of patients.

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