Selective Wee1 Inhibitors Led to Antitumor Activity <i>In Vitro</i> and Correlated with Myelosuppression

Guler, Satenig; DiPoto, Maria C.; Crespo, Alejandro; Caldwell, Richard D.; Doerfel, Benjamin; Grossmann, Nina; Ho, Kevin; Huck, Bayard R.; Jones, Christopher C.; Lan, Ruoxi; Müsil, Djordje; Potnick, Justin R.; Schilke, Heike; Sherer, Brian; Simon, Stephanie; Sirrenberg, Christian; Zhang, Zhuo; Liu-Bujalski, Lesley

doi:10.1021/acsmedchemlett.2c00481

Cited by 6 publications

(9 citation statements)

References 35 publications

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“…Cyclic alkenes ( 67a ) retained WEE1 activity while improving selectivity against PLK1. Other unsaturated and saturated groups displayed decreased WEE1 activity . Furthermore, this study determined myelosuppression as an on-target consequence (independent of PLK1 inhibition) of WEE1 inhibition using the Colony forming unit-megakaryocyte assay (CFU-Mk) .…”

Section: Small Molecule Inhibitors Of Wee1 Kinasementioning

confidence: 99%

“…Excruciating grade 4 or 3 myelosuppression is observed in almost all trials, limiting AZD1775’s potential as an ideal candidate . Initially, the toxicity profile of AZD1775 was inseparable from its off-target activity against PLK1, but recent studies and trials using more selective analogue ZN-c3 also showed treatment-related adverse events, including all grades of GI toxicities, ≥ grade 3 neutropenia, and other hematological toxicities. , Additionally, a 2023 study to optimize selective AZD1775 analogues identified thrombocytopenia as an inevitable consequence of WEE1 inhibition and not PLK inhibition, asserting thrombocytopenia as an on-target toxicity . On the other hand, IMP7068 exhibited negligible DLTs and treatment-related adverse events (TRAEs), including grade 1/2 increased levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and grade 1/2 diarrhea, which are tolerable .…”

Section: Adverse Events Of Existing Clinical Candidatesmentioning

confidence: 99%

“…Other unsaturated and saturated groups displayed decreased WEE1 activity. 126 Furthermore, this study determined myelosuppression as an on-target consequence (independent of PLK1 inhibition) of WEE1 inhibition using the Colony forming unit-megakaryocyte assay (CFU-Mk). 126 Thus, this study offers a new scope for further optimization.…”

Section: Small Molecule Inhibitors Of Wee1 Kinasementioning

confidence: 99%

“…Figure13. Optimization of AZD1775-based analogues (adopted from Matheson et al;123,124 Qian et al;121 Huang et al;125 and Guler et al126 ).…”

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confidence: 99%

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

et al. 2023

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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.

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Section: Small Molecule Inhibitors Of Wee1 Kinasementioning

confidence: 99%

Section: Adverse Events Of Existing Clinical Candidatesmentioning

confidence: 99%

Section: Small Molecule Inhibitors Of Wee1 Kinasementioning

confidence: 99%

“…Figure13. Optimization of AZD1775-based analogues (adopted from Matheson et al;123,124 Qian et al;121 Huang et al;125 and Guler et al126 ).…”

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

et al. 2023

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“…The tyrosine kinase WEE1 is highly homologous to MYT1 and regulates the activity of both CDK1 and CDK2 through Tyr15-phosphorylation of CDK1, thereby controlling intra-S, G2/M, and M phase checkpoints. − WEE1 inhibitors have been reported to exhibit an on-target thrombocytopenia effect, − and the most advanced WEE1 inhibitor, AZD1775 , was suspended in phase 2 clinical trials due to dose-limiting toxicity caused by myelosuppression. − As WEE1 is ubiquitously expressed in somatic cells and MYT1 expression is low in healthy cells and was only found elevated in paired acute myeloid leukemia and testicular germ cell tumors, limiting off-target inhibition of WEE1 is critically important in the design of novel MYT1 inhibitors …”

Section: Introductionmentioning

confidence: 99%

Discovery of Tetrahydropyrazolopyrazine Derivatives as Potent and Selective MYT1 Inhibitors for the Treatment of Cancer

Wang,

Liu

et al. 2023

J. Med. Chem.

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Breast and gynecological cancers are among the leading causes of death in women worldwide, illustrating the urgent need for innovative treatment options. We identified MYT1 as a promising new therapeutic target for breast and gynecological cancer using PandaOmics, an AI-driven target discovery platform. The synthetic lethal relationship of MYT1 in tumor cell lines with CCNE1 amplification enhanced this rationale. Through structurebased drug design, we developed a series of novel, potent, and highly selective inhibitors specifically targeting MYT1. Importantly, our lead compound, featuring a tetrahydropyrazolopyrazine ring, exhibits remarkable selectivity over WEE1, a related kinase associated with bone marrow suppression upon inhibition. Optimization of potency and physical properties resulted in the discovery of compound 21, a novel MYT1 inhibitor, exhibiting optimal pharmacokinetic properties and promising in vivo antitumor efficacy.

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Synthesis and biological evaluation of (2‐aminosulfonylpyridin‐6‐yl)pyrazolopyrimidinone derivatives as Wee1 inhibitors for cancer treatment

Kim,

Jung,

Lee

et al. 2023

Bulletin Korean Chem Soc

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For an analog‐based design of novel Wee1 inhibitors, we profiled in vitro ADMET and in vivo PK properties of adavosertib. Based on the properties of adavosertib, we aimed to improve its metabolic stability by designing a novel target compound 1a with an aminosulfonyl group instead of the 2‐hydroxypropan‐2‐yl moiety in adavosertib. Derivatives of target compound 1a were synthesized and evaluated for Wee1 enzyme inhibition and liver microsomal phase I stability. We identified compound 1a as a sub‐nanomolar Wee1 inhibitor and 10 additional compounds with one‐digit nanomolar Wee1 inhibitory activity, among which seven compounds including 1a exhibited improved metabolic stabilities compared with adavosertib. However, MDA‐MB‐231 cell growth inhibitory activities of all synthesized compounds and Wee1 substrate phosphorylation inhibitory activities of selected compounds were inferior to adavosertib overall. Moreover, the representative compound 1a exhibited low permeability, which may be the reason for the low cellular activities of compound 1a.

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Selective Wee1 Inhibitors Led to Antitumor Activity In Vitro and Correlated with Myelosuppression

Cited by 6 publications

References 35 publications

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

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

Discovery of Tetrahydropyrazolopyrazine Derivatives as Potent and Selective MYT1 Inhibitors for the Treatment of Cancer

Synthesis and biological evaluation of (2‐aminosulfonylpyridin‐6‐yl)pyrazolopyrimidinone derivatives as Wee1 inhibitors for cancer treatment

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