Poster Presentation 11th Annual Conference of the International Chemical Biology Society 2022

The synthesis of novel WEE1 kinase inhibitors for the treatment of cancer (#168)

Joel L Syphers 1 , Susan Woods 2 , Josephine Wright 2 , Daniel Worthley 2 , Yi Sing Gee 1 , Ramesh Mudududdla 1 , Da Qing Che 3 , Siddhartha Mukherjee 4 , Jonathan Baell 1
  1. Medicinal Chemistry, Monash University, Melbourne, VIC, Australia
  2. Biomedical Science, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
  3. Medicinal Chemistry, Julius Pharma, Hang Zhou, Not US or Canada, China
  4. Chemistry, Columbia Univeristy, New York, United States of America

WEE1 kinase has been of cumulative interest in the past decade as a validated drug target for the treatment of cancer.1 WEE1 kinase is a key regulator of the G2/S DNA repair checkpoints of the cell cycle and with many human malignancies harbouring mutations in their G1 DNA repair checkpoint, they must rely on intact G2/S DNA repair checkpoints for successful cancer cell replication.1 Therefore, inhibition of WEE1 kinase can selectively sensitise G1 DNA repair checkpoint deficient cancer cells.1

AZD1775 is a potent inhibitor (IC50 of 41 nM) of WEE1 kinase and was the frontrunner clinical candidate in the race to become the first WEE1 inhibitor approved.2 Although having promising clinical results (Phase 1 & 2), it was noted that patients had tolerability issues, mainly due to protein selectivity, and consequently was discontinued after more than 10 years in the trials.3 Many research groups around the world had become aware of such complications through the past few years and started SAR studies using the chemical structure of AZD1775 as a starting point, including our group.3

The chemical structure of the benchmark compound contains a pyrazolopyrimidone scaffold, an isopropyl alcohol substituted aryl head group and a N-methyl piperazine substituted aryl tail group. A comprehensive SAR analysis of all three sections of AZD1775 was undertaken, resulting with the lead compound which has a tetrahydroisoquinoline tail group moiety. Fortunately, the lead compound was very potent and achieved an IC50 of 14 nM against WEE1 kinase. Bioactivities of the benchmark compound, the lead compound and others, were assessed in cancer organoids (MS326). The lead compound achieved more than a 2-fold increase of activity (IC50 of 0.060 µM) in comparison with the AZD1775 (IC50 of 0.16 µM). These promising results showcase that newer and potent analogues can be discovered and ultimately allow for medicinal chemistry groups around the world to join the race to push a novel WEE1 kinase inhibitor to FDA-approved status.

 

  1. Do, K.; Doroshow, J. H.; Kummar, S. Wee1 kinase as a target for cancer therapy. Cell Cycle 2013, 12, 3348-3353.
  2. atheson, C. J.; Casalvieri, K. A.; Backos, D. S.; Reigan, P. Development of Potent Pyrazolopyrimidinone-Based WEE1 Inhibitors with Limited Single-Agent Cytotoxicity for Cancer Therapy. ChemMedChem 2018, 13, 1681-1694.
  3. Huang, P. Q.; Boren, B. C.; Hegde, S. G.; Liu, H.; Unni, A. K.; Abraham, S.; Hopkins, C. D.; Paliwal, S.; Samatar, A. A.; Li, J.; Bunker, K. D. Discovery of ZN-c3, a Highly Potent and Selective Wee1 Inhibitor Undergoing Evaluation in Clinical Trials for the Treatment of Cancer. Journal of Medicinal Chemistry 2021, 64, 13004-13024.