Pseudokinases: Prospects for expanding the therapeutic targets armamentarium

Devang, Nayana; Pani, Adyashree; Rajanikant, G. K.

doi:10.1016/bs.apcsb.2020.09.004

Cited by 2 publications

(8 citation statements)

References 178 publications

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“…Collective results have revealed that HER3 is essential for HER2-dependent breast cancer cell survival and promotes resistance to EGFR-and HER2-targeted therapies. 18 The importance of HER3 in cancer development and resistance has stimulated the effort to develop small-molecule HER3 modulators. In 2014, Gray and co-workers reported a hydrophobic tag (HyT)-based HER3 degrader, TX-2−121−1 (1, Figure 1), which induced partial degradation of HER3 and inhibited heterodimerization of HER3−HER2 and HER3− hepatocyte growth factor receptor (c-Met).…”

Section: T H Imentioning

confidence: 99%

“…Several extensive reviews about pseudokinases have been published recently. 14,17,18 However, progress on characterization and small-molecule regulation of the noncatalytic functions of kinases is rarely discussed. Notably, recent investigation implies that the scaffolding functions of several kinases are heavily involved in the limited clinical efficacy and/ or resistance of the kinase inhibitor drugs.…”

Section: T H Imentioning

confidence: 99%

“…The scaffolding functions of kinases, which are independent of their enzymatic activities, have been demonstrated to play a critical role in multiple cellular signaling and cell fate controls. − The extreme examples are pseudokinases which are characterized by the presence of inactivating mutations in the key catalytic residues of kinase domains while preserving the overall structures. − Although pseudokinases lack catalytic activity, they represent approximately 10% of the human kinome and are indispensable for regulation of multiple cellular functions. One of the well-characterized pseudokinases is the human epidermal growth factor receptor (HER/EGFR) family member HER3 .…”

Section: Introductionmentioning

confidence: 99%

“…Although HER3 is catalytically impaired, it can allosterically activate EGFR and HER2 via forming heterodimers with the corresponding partner proteins. Collective results have revealed that HER3 is essential for HER2-dependent breast cancer cell survival and promotes resistance to EGFR- and HER2-targeted therapies . The importance of HER3 in cancer development and resistance has stimulated the effort to develop small-molecule HER3 modulators.…”

Section: Introductionmentioning

confidence: 99%

“…These examples clearly underscore the critical roles of the kinase scaffold in different cellular signal transductions. Several extensive reviews about pseudokinases have been published recently. ,, However, progress on characterization and small-molecule regulation of the noncatalytic functions of kinases is rarely discussed. Notably, recent investigation implies that the scaffolding functions of several kinases are heavily involved in the limited clinical efficacy and/or resistance of the kinase inhibitor drugs. , Herein, we would like to summarize the recent progress on characterization and small-molecule modulation of the noncatalytic functions of kinases.…”

Section: Introductionmentioning

confidence: 99%

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Targeting the Non-Catalytic Functions: a New Paradigm for Kinase Drug Discovery?

et al. 2022

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Protein kinases have been highly fruitful targets for cancer drug discovery in the past two decades, while most of these drugs bind to the “adenosine triphosphate (ATP)-site” and inhibit kinase catalytic activity. Recently, accumulated evidence suggests that kinases possess functions beyond catalysis through their scaffolds, and the scaffolding functions could play critical roles in multiple cellular signaling and cell fate controls. Small molecules modulating the noncatalytic functions of kinases are rarely reported but emerge as new promising therapeutic strategies for various diseases. Herein, we summarize the characterized noncatalytic functions of kinases, and highlight the recent progress on developing small-molecule modulators of the noncatalytic functions of kinases. Mechanisms and characteristics of different kinds of modulators are also discussed. It is also speculated that targeting the noncatalytic functions would represent a new direction for kinase-based drug discovery.

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Section: T H Imentioning

confidence: 99%

Section: T H Imentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Targeting the Non-Catalytic Functions: a New Paradigm for Kinase Drug Discovery?

et al. 2022

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Recent insights into the therapeutic strategies targeting the pseudokinase PTK7 in cancer

Dessaux,

Ganier,

Guiraud

et al. 2024

Oncogene

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The generation of drugs counteracting deregulated protein kinases has been a major focus in cancer therapy development. Breakthroughs in this effort have produced many therapeutic agents to the benefit of patients, mostly through the development of chemical or antibody-based drugs targeting active kinases. These strategies are challenged when considering catalytically inactive protein kinases (or pseudokinases), which represent 10% of the human kinome with many of relevance in cancer. Among the so-called pseudotyrosine kinases, the PTK7 receptor tyrosine kinase (RTK) stands as a bona fide target overexpressed in several solid tumors and hematological malignancies and linked to metastasis, poor prognosis, and resistance to treatment. Despite the lack of catalytic activity, PTK7 has signaling capacities through heterodimerization with active RTKs and offers pharmacological targeting opportunities through its inactive kinase domain. Moreover, PTK7-targeting strategies based on antibody-drug conjugates, aptamers, and CAR-T cell-based therapies have demonstrated encouraging results in preclinical and clinical settings. We review the most recent data assigning to PTK7 a prominent role in cancer progression as well as current preclinical and clinical targeting strategies against RTK family pseudokinases including PTK7.

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Pseudokinases: Prospects for expanding the therapeutic targets armamentarium

Cited by 2 publications

References 178 publications

Targeting the Non-Catalytic Functions: a New Paradigm for Kinase Drug Discovery?

Targeting the Non-Catalytic Functions: a New Paradigm for Kinase Drug Discovery?

Recent insights into the therapeutic strategies targeting the pseudokinase PTK7 in cancer

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