更新于：2024-11-01

PITSLRE subfamily

更新于：2024-11-01

基本信息

别名-

简介-

关联

项与 PITSLRE subfamily 相关的药物

OTS-964

靶点

TOPK

作用机制

PITSLRE subfamily inhibitors [+1]

在研机构

OncoTherapy Science, Inc.

原研机构

OncoTherapy Science, Inc.

在研适应症

肿瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

ZNL-05-044

靶点

CDK11A

作用机制

CDK11A 抑制剂

在研机构

Stanford University

原研机构

Stanford University

在研适应症

肿瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 PITSLRE subfamily 相关的临床结果

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100 项与 PITSLRE subfamily 相关的转化医学

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0 项与 PITSLRE subfamily 相关的专利（医药）

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项与 PITSLRE subfamily 相关的文献（医药）

2022-12-02·Molecular Cancer Research

Molecular Profile Changes in Patients with Castrate-Resistant Prostate Cancer Pre- and Post-Abiraterone/Prednisone Treatment

Article

作者: Kohli, Manish ; Bhargava, Vipul ; Vedell, Peter T. ; Gormley, Michael ; Bryce, Alan H. ; Kalari, Krishna R. ; Tan, Winston ; Sinnwell, Jason P. ; Jimenez, Raphael E. ; Li, Ying ; Qin, Sisi ; Dehm, Scott M. ; Hillman, David W. ; Carlson, Rachel E. ; Weinshilboum, Richard M. ; Sicotte, Hugues ; Wang, Liewei

AbstractWe identified resistance mechanisms to abiraterone acetate/prednisone (AA/P) in patients with metastatic castration-resistant prostate cancer (mCRPC) in the Prostate Cancer Medically Optimized Genome-Enhanced Therapy (PROMOTE) study.We analyzed whole-exome sequencing (WES) and RNA-sequencing data from 83 patients with metastatic biopsies before (V1) and after 12 weeks of AA/P treatment (V2). Resistance was determined by time to treatment change (TTTC).At V2, 18 and 11 of 58 patients had either short-term (median 3.6 months; range 1.4–4.5) or long-term (median 29 months; range 23.5–41.7) responses, respectively. Nonresponders had low expression of TGFBR3 and increased activation of the Wnt pathway, cell cycle, upregulation of AR variants, both pre- and posttreatment, with further deletion of AR inhibitor CDK11B posttreatment. Deletion of androgen processing genes, HSD17B11, CYP19A1 were observed in nonresponders posttreatment. Genes involved in cell cycle, DNA repair, Wnt-signaling, and Aurora kinase pathways were differentially expressed between the responder and non-responder at V2. Activation of Wnt signaling in nonresponder and deactivation of MYC or its target genes in responders was detected via SCN loss, somatic mutations, and transcriptomics. Upregulation of genes in the AURKA pathway are consistent with the activation of MYC regulated genes in nonresponders. Several genes in the AKT1 axis had increased mutation rate in nonresponders. We also found evidence of resistance via PDCD1 overexpression in responders.Implications:Finally, we identified candidates drugs to reverse AA/P resistance: topoisomerase inhibitors and drugs targeting the cell cycle via the MYC/AURKA/AURKB/TOP2A and/or PI3K_AKT_MTOR pathways.

2022-10-01·Molecular Biology Reports

Mitochondrial ribosomal small subunit (MRPS) MRPS23 protein–protein interaction reveals phosphorylation by CDK11-p58 affecting cell proliferation and knockdown of MRPS23 sensitizes breast cancer cells to CDK1 inhibitors

Article

作者: Rajkumar, Thangarajan ; Oviya, Revathi Paramasivam ; Ramanathan, Priya ; Jayavelu, Subramani ; Ramachandran, Balaji ; Gopal, Gopisetty ; Thangaretnam, Krishna Priya

BACKGROUNDPost-translational modification of some mitoribosomal proteins has been found to regulate their functions. MRPS23 has been reported to be overexpressed in various cancers and has been predicted to be involved in increased cell proliferation. Furthermore, MRPS23 is a driver of luminal subtype breast cancer. However, its exact role and function in cancer remains unknown. METHODS AND RESULTS: Our previous study identified protein-protein interactions involving MRPS23 and CDK11A. In this study, we confirmed the interaction of MRPS23 with the p110 and p58 isoforms of CDK11A. Phosphoprotein enrichment studies and in vitro kinase assay using CDK11A/cyclin D3 followed by MALDI-ToF/ToF analysis confirmed the phosphorylation of MRPS23 at N-terminal serine 11 residue. Breast cancer cells expressing the MRPS23 (S11G) mutant showed increased cell proliferation, increased expression of PI3-AKT pathway proteins [p-AKT (Ser47), p-AKT (Thr308), p-PDK (Ser241) and p-GSK-3β (Ser9)] and increased antiapoptotic pathway protein expression [Bcl-2, Bcl-xL, p-Bcl2 (Ser70) and MCL-1] when compared with the MRPS23 (S11A) mutant-overexpressing cells. This finding indicated the role of MRPS23 phosphorylation in the proliferation and survival of breast cancer cells. The correlation of inconsistent MRPS23 phosphoserine 11 protein expression with CDK11A in the breast cancer cells suggested phosphorylation by other kinases. In vitro kinase assay showed that CDK1 kinase also phosphorylated MRPS23 and that inhibition using CDK1 inhibitors lowered phospho-MRPS23 (Ser11) levels. Additionally, modulating the expression of MRPS23 altered the sensitivity of the cells to CDK1 inhibitors.CONCLUSIONIn conclusion, phosphorylation of MRPS23 by mitotic kinases might potentially be involved in the proliferation of breast cancer cells. Furthermore, MRPS23 can be targeted for sensitizing the breast cancer cells to CDK1 inhibitors.

2022-05-13·Cancer Biomarkers3区 · 医学

Expression pattern and prognostic significance of CDKs in breast cancer: An integrated bioinformatic study

3区 · 医学

Article

作者: Sofi, Shazia ; Mir, Manzoor A. ; Mehraj, Umar ; Alshehri, Bader

BACKGROUND: Globally, breast cancer (BC) has become one of the most prevalent malignancies and the leading cause of tumor-related deaths among women. Dysregulation of the cell cycle is a well-known hallmark of cancer development and metastasis. CDKs are essential components of the cell-cycle regulatory system with aberrant expression in a variety of cancers, including BC. In the development of targeted cancer treatment, reestablishing the regulation of the cell cycle by modulation of CDKs has emerged as a promising approach. METHODS: Herein, we used a bioinformatic approach to assess the expression pattern, prognostic and diagnostic importance, and clinical relevance of CDKs in BC. Additionally, we conducted a functional enrichment analysis of deregulated CDKs using the STRING and KEGG databases to delineate the role of CDKs in breast tumorigenesis. RESULTS: Gene expression analysis revealed substantial deregulation of CDKs in BC, with CDK1, CDK11A, and CDK18 showing a fold change of >± 1.5. Also, metastatic tumors showed high expression of CDK1 in the single cell RNA sequencing analysis of primary and metastatic breast tumors. Additionally, it was found that dysregulated CDK expression affects overall survival (OS) and relapse-free survival (RFS) of BC patients. CONCLUSION: The study’s multimodal analytical methodologies imply that modulating CDKs for BC treatment is a promising approach.