Discovery of thalidomide-based PROTAC small molecules as the highly efficient SHP2 degraders

Yang, Xiao; Wang, Zhijia; Yuan, Peng; Song, Ning; Xu, Lei; Feng, Bo; Wang, Hanlin; Luo, Xiaomin; Hu, Xiaobei; Qiu, Xiaohui; Feng, Huijin; Yang, Yaxi; Zhou, Yubo; Li, Jingya; Zhou, Bing

doi:10.1016/j.ejmech.2021.113341

Cited by 57 publications

(45 citation statements)

References 34 publications

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“…Whereas some IMiD-dependent PROTACs can induce detectable degradation of target proteins within 0.5 h, several hours of treatment with R1-5C are required before significant depletion of SHP2 is observed in either cell line. Although the origin of the slower onset of SHP2 degradation is not clear, the other recently reported, SHP2-targeting PROTACs also exhibit similar degradation kinetics based on Western blot analysis, independent of whether degradation is mediated by VHL 33 or CRBN 34 .…”

Section: Discussionmentioning

confidence: 75%

“…PROTAC featuring an SHP2 allosteric site-binding warhead and the CRBN-targeting IMiD pomalidomide. R1-5C expands the range of PROTACs targeting SHP2, which currently include a VHL-targeting PROTAC 33 and the Novartis clinical candidate TNO155 coupled to thalidomide 34 .…”

Section: Discussionmentioning

confidence: 99%

“…(gene name PTPN11) is the only protein that shows a statistically significant reduction in abundance at time points from 4-8 hours, before secondary effects of SHP2 inhibition can be observed. By comparison, the selectivity of other reported SHP2-targeting PROTACS has not yet been assessed using whole proteomic studies 33,34 .…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

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Targeted degradation of the oncogenic phosphatase SHP2

Vemulapalli

Donovan

Seegar

et al. 2021

Preprint

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“…Considering that the SHP2 degrader with the CRBN ligand could well supplement the degrader using VHL ligand, based on a SHP2 ligand (77, Figure 25) similar to TNO155 (76, Figure 25), Zhou's team designed and synthesized a series of SHP2 degrader using thalidomide as warhead by optimizing the linker. [116] ZB-S-29 (78, Figure 25) could effectively induce the degradation of SHP2 protein in a time-dependent and dose-dependent manner, with the DC50 of 6.0 nM. Interestingly, at about the same time, another CRBN-based SHP2 PROTAC was also reported.…”

Section: Protac Degrader Of Shp2 Acting On Allosteric Sitesmentioning

confidence: 94%

Cross the Undruggable Barrier, the Development of SHP2 Inhibitors: From Catalytic Site Inhibitors to Allosteric Inhibitors

Guo

Dong

et al. 2021

ChemistrySelect

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SHP2 (Src homology-2 domain-containing protein tyrosine phosphatase-2) is a unique protein tyrosine phosphatase(PTP)encoded by the PTPN11 gene, which is composed of two SH2 domains (N-SH2, C-SH2) and the PTP domain. SHP2 is essential in several oncogenic signaling pathways (especially Ras/Raf/ MAPK) and has a wide range of mutations in various cancers. Therefore, the development of inhibitors of SHP2 has become the focus of anticancer research in recent years. Initially, the researchers hoped to directly inhibit SHP2 activity by targeting its catalytic sites like other PTP inhibitors' development.However, the high homology and strong positivity of PTP catalytic sites bring great difficulties in developing such inhibitors. Finally, in 2015, a compact molecule (SHP099) passed the undruggable barrier of SHP2 through the allosteric tunnel. In this paper, the development of SHP2 inhibitors in recent years will be reviewed to transition from catalytic site inhibitors to allosteric inhibitors to provide suggestions for the development and application of SHP2 inhibitors and other PTP inhibitors.

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“…What's more, taking advantage of haloPROTACs, a ligand-inducible tractable affinity-directed protein missile system (L-AdPROM), in which aHRAS conjugated to the Halo-tag and tagged with a FLAG reporter, successfully degraded RAS and reduce the RAS-driven signaling in A549 cells [199]. In addition, PROTACs regarding some targets in RAS signaling pathway, such as MEK, PDEδ, TBK1 and SHP2, also successfully degraded the corresponding targets and suppressed the RAS signaling in vitro or in vivo [200][201][202][203].…”

Section: Other Strategies Of Targeting Mutant Rasmentioning

confidence: 99%

Emerging strategies to target RAS signaling in human cancer therapy

et al. 2021

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RAS mutations (HRAS, NRAS, and KRAS) are among the most common oncogenes, and around 19% of patients with cancer harbor RAS mutations. Cells harboring RAS mutations tend to undergo malignant transformation and exhibit malignant phenotypes. The mutational status of RAS correlates with the clinicopathological features of patients, such as mucinous type and poor differentiation, as well as response to anti-EGFR therapies in certain types of human cancers. Although RAS protein had been considered as a potential target for tumors with RAS mutations, it was once referred to as a undruggable target due to the consecutive failure in the discovery of RAS protein inhibitors. However, recent studies on the structure, signaling, and function of RAS have shed light on the development of RAS-targeting drugs, especially with the approval of Lumakras (sotorasib, AMG510) in treatment of KRASG12C-mutant NSCLC patients. Therefore, here we fully review RAS mutations in human cancer and especially focus on emerging strategies that have been recently developed for RAS-targeting therapy.

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Discovery of thalidomide-based PROTAC small molecules as the highly efficient SHP2 degraders

Cited by 57 publications

References 34 publications

Targeted degradation of the oncogenic phosphatase SHP2

Targeted degradation of the oncogenic phosphatase SHP2

Cross the Undruggable Barrier, the Development of SHP2 Inhibitors: From Catalytic Site Inhibitors to Allosteric Inhibitors

Emerging strategies to target RAS signaling in human cancer therapy

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