482P Safety, pharmacokinetic (PK), and pharmacodynamic profiles of the WEE1 inhibitor IMP7068 in patients (pts) with advanced solid tumors

Lin, Chung‐Ying; Grewal, Jobanpreet; Sommerhalder, D.; Bai, L-Y.; Li, Guang-Jie; Schneider, R.; Shen, L.; Yeh, Y-M; Yin, R.; Hc, Hsu; Baranda, J.C.; Cc, Hsieh; Cai, S.X.; Tian, Yangtao; Ma, N.; Xia, H.; Zhang, C.; Li, B.; Zhang, M.; Yu, Z.

doi:10.1016/j.annonc.2022.07.610

Cited by 1 publication

(2 citation statements)

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“… 135 Selective small‐molecule oral inhibitors IMP7068 and ZN‐c3 have recently communicated promising anti‐tumour activity in small dose‐escalating cohorts (CBR 64% with ORR 0% and CBR 44% with ORR 13%, respectively) and a tolerable safety profile (seven grade ≥3 events reported in three out of 24 patients receiving IMP7068). 136 , 137 , 138 , 139 Similarly, Debio 0123 has been shown tolerable with three grade ≥3 thrombocytopenia events among 38 patients as the most frequent high‐grade TEAE. 140 These novel inhibitors will eventually inform the potential of WEE1 as a pharmacological target in BC.…”

Section: G2/m Phase Transitionmentioning

confidence: 99%

“…While the development of adavosertib has focused principally on ovarian cancer, where it has reached phase 2 testing in combination with chemotherapy, there are other WEE1i with similar preclinical activity and expected superior safety profiles based on ongoing phase 1 trials 135 . Selective small‐molecule oral inhibitors IMP7068 and ZN‐c3 have recently communicated promising anti‐tumour activity in small dose‐escalating cohorts (CBR 64% with ORR 0% and CBR 44% with ORR 13%, respectively) and a tolerable safety profile (seven grade ≥3 events reported in three out of 24 patients receiving IMP7068) 136–139 . Similarly, Debio 0123 has been shown tolerable with three grade ≥3 thrombocytopenia events among 38 patients as the most frequent high‐grade TEAE 140 .…”

Section: G2/m Phase Transitionmentioning

confidence: 99%

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Seize the engine: Emerging cell cycle targets in breast cancer

Fuentes‐Antrás,

Bedard,

Cescon

2024

Clinical & Translational Med

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Breast cancer arises from a series of molecular alterations that disrupt cell cycle checkpoints, leading to aberrant cell proliferation and genomic instability. Targeted pharmacological inhibition of cell cycle regulators has long been considered a promising anti‐cancer strategy. Initial attempts to drug critical cell cycle drivers were hampered by poor selectivity, modest efficacy and haematological toxicity. Advances in our understanding of the molecular basis of cell cycle disruption and the mechanisms of resistance to CDK4/6 inhibitors have reignited interest in blocking specific components of the cell cycle machinery, such as CDK2, CDK4, CDK7, PLK4, WEE1, PKMYT1, AURKA and TTK. These targets play critical roles in regulating quiescence, DNA replication and chromosome segregation. Extensive preclinical data support their potential to overcome CDK4/6 inhibitor resistance, induce synthetic lethality or sensitise tumours to immune checkpoint inhibitors. This review provides a biological and drug development perspective on emerging cell cycle targets and novel inhibitors, many of which exhibit favourable safety profiles and promising activity in clinical trials.

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