Discovery of a first-in-class CDK2 selective degrader for AML differentiation therapy

Wang, Liguo; Shao, Xuejing; Zhong, Tianbai; Wu, Yue; Xu, Aixiao; Sun, Xiaohong; Gao, Hongying; Liu, Yongbo; Lan, Tianlong; Yan, Tao; Xue, Tao; Du, Wenxin; Wang, Wei; Chen, Yingqian; Li, Ting; Meng, Xianbin; Deng, Haiteng; Yang, Bo; He, Qiaojun; Rao, Yu

doi:10.1038/s41589-021-00742-5

Cited by 90 publications

(69 citation statements)

References 48 publications

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“…Accelerated cell-cycle progression is a key hallmark of malignant proliferation of cancer cells [ 39 , 40 ], and targeted inhibition of cell cycle is widely considered to be an effective clinical anti-tumor strategy [ 41 , 42 ]. Flow cytometry analysis revealed that siRNA-mediated silencing of LINC00022 induced changes in the cell-cycle distribution of KYSE150 and TE1 cells, resulting in an increased proportion of G0/G1 cells and a decreased ratio of G2/M cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Mechanistically, continuous activation of cell cycle signal is one of the predominant biological characteristics of malignant tumor progression, and anti-tumor drugs based on targeting cell-cycle regulators, such as CDK inhibitors, have been proved to be effective [ 42 , 57 ]. However, inherent or acquired resistance of cancer cells to CDK inhibitors has become a major obstacle to their clinical application [ 58 , 59 ].…”

Section: Discussionmentioning

confidence: 99%

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RNA m6A demethylase FTO-mediated epigenetic up-regulation of LINC00022 promotes tumorigenesis in esophageal squamous cell carcinoma

Cui

Zhang

et al. 2021

J Exp Clin Cancer Res

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Background Long non-coding RNA (LncRNA) controls cell proliferation and plays a significant role in the initiation and progression of esophageal squamous cell carcinoma (ESCC). N6-methyladenosine (m6A) modification now is recognized as a master driver of RNA function to maintain homeostasis in cancer cells. However, how m6A regulates LncRNA function and its role in tumorigenesis of ESCC remain unclear. Methods Multiple ESCC datasets were used to analyze gene expression in tumor tissues and normal tissues. Kaplan-Meier method and the ROC curve were conducted to evaluate the prognostic value and diagnostic value of LINC00022 in ESCC, respectively. Both gain-of-function and loss-of-function experiments were employed to investigate the effects of LINC00022 on ESCC growth in vitro and in vivo. Bioinformatics analysis, colorimetric m6A assay, RIP, MeRIP and co-IP was performed to explore the epigenetic mechanism of LINC00022 up-regulation in ESCC. Results Here we report that m6A demethylation of LncRNA LINC00022 by fat mass and obesity-associated protein (FTO) promotes tumor growth of ESCC in vivo. Clinically, we revealed that LINC00022 was up-regulated in primary ESCC samples and was predictive of poor clinical outcome for ESCC patients. Mechanistically, LINC00022 directly binds to p21 protein and promotes its ubiquitination-mediated degradation, thereby facilitating cell-cycle progression and proliferation. Further, the elevated FTO in ESCC decreased m6A methylation of LINC00022 transcript, leading to the inhibition of LINC00022 decay via the m6A reader YTHDF2. Over-expression of FTO was shown to drive LINC00022-dependent cell proliferation and tumor growth of ESCC. Conclusions Thus, this study demonstrated m6A-mediated epigenetic modification of LncRNA contributes to the tumorigenesis in ESCC and LINC00022, specific target of m6A, serves as a potential biomarker for this malignancy.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

RNA m6A demethylase FTO-mediated epigenetic up-regulation of LINC00022 promotes tumorigenesis in esophageal squamous cell carcinoma

Cui

Zhang

et al. 2021

J Exp Clin Cancer Res

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“…The CRBN E3 ligase ligands (pomalidomide, lenalidomide and thalidomide, collectively referred to as IMiDs) have been successfully employed in the design of a wide range of PROTACs to degrade various proteins [23][24][25][26] . In order to develop an effective SHP2 PROTAC, therefore, we first designed a series of compounds designed to tether SHP099 to the IMiD pomalidomide.…”

Section: Resultsmentioning

confidence: 99%

Targeted degradation of the oncogenic phosphatase SHP2

Vemulapalli

Donovan

Seegar

et al. 2021

Preprint

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SHP2 is a protein tyrosine phosphatase that plays a critical role in the full activation of the Ras/MAPK pathway upon stimulation of receptor tyrosine kinases (RTKs), which are frequently amplified or mutationally activated in human cancer. In addition, activating mutations in SHP2 result in developmental disorders and hematologic malignancies. Several allosteric inhibitors have been developed for SHP2 and are currently in clinical trials. Here, we report the development and evaluation of a SHP2 PROTAC created by conjugating RMC-4550 with pomalidomide using a PEG linker. This molecule is highly selective for SHP2, induces degradation of SHP2 in leukemic cells at sub-micromolar concentration, inhibits MAPK signaling, and suppresses cancer cell growth. SHP2 PROTACs serve as an alternative strategy for targeting ERK-dependent cancers and are useful tools alongside allosteric inhibitors for dissecting the mechanisms by which SHP2 exerts its oncogenic activity.

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“…In 2021, our group reported that we used pan-CDK inhibitor JNJ-7706621 ( 59 , Figure 10 ) and pomalidomide as ligands to design a new type of CDK2 selective degrader 2 ( 60 , Figure 10 ), which achieved high selectivity and efficient degradation of CDK2 ( Wang et al, 2021 ). CPS2 had good selectivity and wide application range, and we tried to test more than 10 cell lines and found it can effectively induce the degradation of CDK2 at nanomolar concentrations.…”

Section: Protac Is Expected To Induce the Degradation Of Undruggable Targetsmentioning

confidence: 99%

Opportunities and Challenges of Small Molecule Induced Targeted Protein Degradation

Rao

2021

Front. Cell Dev. Biol.

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Proteolysis targeting chimeras (PROTAC) represents a new type of small molecule induced protein degradation technology that has emerged in recent years. PROTAC uses bifunctional small molecules to induce ubiquitination of target proteins and utilizes intracellular proteasomes for chemical knockdown. It complements the gene editing and RNA interference for protein knockdown. Compared with small molecule inhibitors, PROTAC has shown great advantages in overcoming tumor resistance, affecting the non-enzymatic function of target proteins, degrading undruggable targets, and providing new rapid and reversible chemical knockout tools. At the same time, its challenges and problems also need to be resolved as a fast-developing newchemical biology technology.

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Discovery of a first-in-class CDK2 selective degrader for AML differentiation therapy

Cited by 90 publications

References 48 publications

RNA m6A demethylase FTO-mediated epigenetic up-regulation of LINC00022 promotes tumorigenesis in esophageal squamous cell carcinoma

RNA m6A demethylase FTO-mediated epigenetic up-regulation of LINC00022 promotes tumorigenesis in esophageal squamous cell carcinoma

Targeted degradation of the oncogenic phosphatase SHP2

Opportunities and Challenges of Small Molecule Induced Targeted Protein Degradation

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