Synthetic and Medicinal Chemistry Approaches Toward WEE1 Kinase Inhibitors and Its Degraders

Abstract

WEE1 is a checkpoint kinase critical for mitotic events, especially in cell maturation and DNA repair. Most cancer cells' progression and survival are linked with elevated levels of WEE1 kinase. Thus, WEE1 kinase has become a new promising druggable target. A few classes of WEE1 inhibitors are designed by rationale or structure-based techniques and optimization approaches to identify selective acting anticancer agents. The discovery of the WEE1 inhibitor AZD1775 further emphasized WEE1 as a promising anticancer target. Therefore, the current review provides a comprehensive data on medicinal chemistry, synthetic approaches, optimization methods, and the interaction profile of WEE1 kinase inhibitors. In addition, WEE1 PROTAC degraders and their synthetic procedures, including a list of noncoding RNAs necessary for regulation of WEE1, are also highlighted. From the standpoint of medicinal chemistry, the contents of this compilation serve as an exemplar for the further design, synthesis, and optimization of promising WEE1-targeted anticancer agents.

Synergistic interactions of cytarabine-adavosertib in leukemic cell lines proliferation and metabolomic endpoints

“…Hence, the combinatorial synergistic efficacy of cytarabine-adavosertib in Jurkat and CCRF-CEM may also be due to the relative expression or activation states of the WEE1 target proteins CDC2 and CDK1 [ 53 ]. Our findings are also be consistent with the conclusion that the role of WEE1 in cells with accumulated DNA damage extends beyond regulation of CDK1 and the G2/M checkpoint [ 53 ] such as the recently established role of CDK2 in G1/S arrest [ 11 , 54 ].…”

Live cell screening to identify RNA-binding small molecule inhibitors of the pre-let-7–Lin28 RNA–protein interaction

“…58 The carbonyl group in the bicyclic pyrimido-pyridazinone has also been shown to engage with the Asn376 residue of the Wee1 gatekeeper region, further contributing to kinase activity and selectivity. 58 In our hands, SID-415260 inhibited Wee1 with an IC 50 value of 35 nM across a panel of 264 kinases with an additional 18 kinases having measured IC 50 values between 298 nM and 1 μM (Table S4†). The promiscuity of this compound was anticipated based on the presence of the aminopyrimidine core which is a common hinge-binding motif found in many multi-kinase inhibitors, 59,60 including Wee1 kinase inhibitors of varying selectivity.…”

“…SID-415260 belongs to a known class of pyrimido[4,5- d ]pyridazine-5(6 H )-ones reported as selective Wee1 kinase inhibitors, with the aminopyrimidine moiety making a key hinge interaction with Cys379 in the Wee1 ATP binding pocket. 58 The carbonyl group in the bicyclic pyrimido-pyridazinone has also been shown to engage with the Asn376 residue of the Wee1 gatekeeper region, further contributing to kinase activity and selectivity. 58 In our hands, SID-415260 inhibited Wee1 with an IC 50 value of 35 nM across a panel of 264 kinases with an additional 18 kinases having measured IC 50 values between 298 nM and 1 μM (Table S4 † ).…”

Kinase Inhibitors and Kinase-Targeted Cancer Therapies: Recent Advances and Future Perspectives

“…WEE1 inhibits CDK through Y15 phosphorylation, thereby arresting the cell cycle at the G2-M and G1-S checkpoints to allow for DNA repair and prevent apoptosis. It is significantly upregulated in various TP53-mutant cancer types, including ovarian cancer, glioblastoma, leukemia, and breast cancer [188]. Adavosertib, a selective oral WEE1 kinase inhibitor, demonstrated efficacy in a Phase II study with recurrent uterine serous carcinoma patients, showing a 29.4% ORR [189].…”