CCNE1 copy number is a biomarker for response to combination WEE1-ATR inhibition in ovarian and endometrial cancer models

Xu, Haineng; George, Erin; Kinose, Yasuto; Kim, Hyoung; Shah, Jennifer; Peake, Jasmine D.; Ferman, Benjamin; Medvedev, Sergey; Murtha, Thomas; Barger, Carter J.; Devins, Kyle M.; D’Andrea, Kurt; Wubbenhorst, Bradley; Schwartz, Lauren E.; Hwang, Wei Ting; Mills, Gordon B.; Nathanson, Katherine L.; Karpf, Adam R.; Drapkin, Ronny; Brown, Eric J.; Simpkins, Fiona

doi:10.1016/j.xcrm.2021.100394

Cited by 43 publications

(61 citation statements)

References 67 publications

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“…Multiple preclinical studies have recently shown that in vitro efficacy of adavosertib does not directly translate into clinical responses to WEE1 inhibition in unselected patient populations. Importantly, increased CCNE1 expression has been consistently correlated with clinical response to WEE1 inhibitors ( 32 – 37 ). Thus, CCNE1 mRNA expression is a patient selection biomarker for WEE1 inhibitor response in patients with cancer at the clinical level.…”

Section: Resultsmentioning

confidence: 99%

WEE1 kinase is a therapeutic vulnerability in CIC-DUX4 undifferentiated sarcoma

Ponce¹,

Thomas²,

Bui³

et al. 2022

JCI Insight

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Section: Resultsmentioning

confidence: 99%

WEE1 kinase is a therapeutic vulnerability in CIC-DUX4 undifferentiated sarcoma

Ponce¹,

Thomas²,

Bui³

et al. 2022

JCI Insight

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“…This assay confirmed the potency boost associated with the 2,6-dimethyl phenol motif of analog 6.compare to both mono methyl analogs 1 and 4. Interestingly, the chloro analogs 17 and 18 without a methyl at R 4 that showed comparable potency in the enzymatic assay (Table 1) were significantly less potent than analog 16 in the cell-based assay despite good cell permeability (analog 17 Caco2 Papp A-B=14.1 x 10 -6 cm/s, efflux ratio (ER) = 1.2; analog 18 Caco2 Papp A-B=18.8 x 10 -6 cm/s, ER=0.4). 2-Chloro phenol analog 16 showed favorable cell potency compared to 2,6-dimethyl phenol analog 6 but such chloro substitution resulted in notable increase in metabolism in a human hepatocyte assay.…”

Section: Compound Structure-activity-relationships and Optimizationmentioning

confidence: 99%

“…3 In contrast, WEE1 phosphorylates tyrosine 15 (Tyr15) of CDK1 and is implicated in the regulation of both CDK1 and CDK2 activity. 4 PKMYT1 function does not appear to be critical in the unperturbed cell cycle whereas WEE1 function is essential for cell cycle progression of cells. 5 However, the absence of functional PKMYT1 in a genetically-vulnerable tumor, such as with CCNE1-amplification, causes cells to lose major checkpoint regulation leading to hyperactive CDK1, unscheduled mitosis and catastrophic DNA damage, ultimately resulting in cell death.…”

Section: Introduction and Biological Rationalementioning

confidence: 98%

“…ESI MS m/z 378.26 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.74 (s, 1H), 8.40 (d, J = 5.2 Hz, 1H), 8.04 -7.92 (m, 3H), 7.79 (d, J = 8.0 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.83 (s, 1H), 4.91 (t, J = 4 4. Hz, 1H), 3.62 (t, J = 6.0 Hz, 2H), 3.52 (t, J = 5.2 Hz, 2H), 1.89 (s, 3H).1-(3-methoxy-2,6-dimethyl-phenyl)pyrrolo[3,2-b]quinoxaline-3-carbonitrile (83).To a solution of 64 (400 mg, 1.16 mmol) in THF (10 mL) was added tert-butyl nitrite (599 mg, 5.81 mmol).…”

mentioning

confidence: 99%

“…ESI MS m/z 348.2 [M + H] + . DMSO-d6) δ 7.94 (dd, J = 8.3, 1.4 Hz, 1H), 7.80 -7.73 (m, 2H), 7.57 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.49 -7.40 (m, 2H), 7.35 (br s, 1H), 7.24 (dd, J = 8.5, 1.1 Hz, 1H), 7.05 (dd, J = 8.0, 1.0 Hz, 1H), 3.91 (s, 3H), 1.85 (s, 3H).2-amino-1-(3-hydroxy-2-methyl-phenyl)pyrrolo[3,2-b]quinoxaline-3-carboxamide(4). Following the procedure used to prepare 3, BBr3 (1M in DCM, 11 mL, 11 mmol) was added to a solution of 77 (990 mg, 2.85 mmol) in DCM (11 mL) and the mixture was stirred for 90 min at RT.…”

mentioning

confidence: 99%

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Discovery of an orally bioavailable and selective PKMYT1 inhibitor RP-6306

Szychowski

Papp

Dietrich

et al. 2022

Preprint

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PKMYT1 is an important regulator of CDK1 phosphorylation and is a compelling therapeutic target for the treatment of certain types of DNA damage response cancers due to its established synthetic lethal relationship with CCNE1 amplification. To date, no selective inhibitors have been reported for this kinase that would allow for investigation of the pharmacological role of PKMYT1 in the treatment of cancer. To address this need we conducted a focused screening effort that identified compound 1 as a weak PKMYT1 inhibitor. Introduction of a dimethylphenol dramatically increased potency on PKMYT1. These dimethylphenol analogs were found to exist as Type III atropisomers that could be separated and profiled as single enantiomers. Structure-based drug design aided by co-crystal structures of several analogs enabled optimization of cell-based potency and kinase selectivity. Parallel optimization of ADME properties led to the identification of potent and selective inhibitors of PKMYT1 with favorable pharmacokinetics. RP-6306 inhibits the phosphorylation of CDK1 Thr14 in vivo in tumor tissue and inhibits CCNE1-amplified tumor cell growth in several preclinical xenograft models. The first-in-class clinical candidate RP-6306 is currently being evaluated in Phase 1 clinical trials (NCT04855656) for treatment of various solid tumors.

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Current insights into the oncogenic roles of lncRNA LINC00355

Shen,

Su,

Pan

et al. 2023

Cancer Innovation

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Long noncoding RNAs (lncRNAs) are a class of nonprotein‐coding transcripts that are longer than 200 nucleotides. LINC00355 is a lncRNA located on chromosome 13q21.31 and is consistently upregulated in various cancers. It regulates the expression of downstream genes at both transcriptional and posttranscriptional levels, including eight microRNAs (miR‐15a‐5p, miR‐34b‐5p, miR‐424‐5p, miR‐1225, miR‐217‐5p, miR‐6777‐3p, miR‐195, and miR‐466) and three protein‐coding genes (ITGA2, RAD18, and UBE3C). LINC00355 plays a role in regulating various biological processes such as cell cycle progression, proliferation, apoptosis, epithelial‐mesenchymal transition, invasion, and metastasis of cancer cells. It is involved in the regulation of the Wnt/β‐catenin signaling pathway and p53 signaling pathway. Upregulation of LINC00355 has been identified as a high‐risk factor in cancer patients and its increased expression is associated with poorer overall survival, recurrence‐free survival, and disease‐free survival. LINC00355 upregulation has been linked to several unfavorable clinical characteristics, including advanced tumor node metastasis and World Health Organization stages, reduced Karnofsky Performance Scale scores, increased tumor size, greater depth of invasion, and more extensive lymph node metastasis. LINC00355 induces chemotherapy resistance in cancer cells by regulating five downstream genes, namely HMGA2, ABCB1, ITGA2, WNT10B, and CCNE1 genes. In summary, LINC00355 is a potential oncogene with great potential as a diagnostic marker and therapeutic target for cancer.

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CCNE1 copy number is a biomarker for response to combination WEE1-ATR inhibition in ovarian and endometrial cancer models

Cited by 43 publications

References 67 publications

WEE1 kinase is a therapeutic vulnerability in CIC-DUX4 undifferentiated sarcoma

WEE1 kinase is a therapeutic vulnerability in CIC-DUX4 undifferentiated sarcoma

Discovery of an orally bioavailable and selective PKMYT1 inhibitor RP-6306

Current insights into the oncogenic roles of lncRNA LINC00355

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