Disrupting the platelet internal membrane via PI3KC2α inhibition impairs thrombosis independently of canonical platelet activation

Selvadurai, Maria V.; Moon, Mitchell J.; Mountford, Simon J.; Ma, Xuelei; Zheng, Zhihai; Jennings, Ian G.; Setiabakti, Natasha Marianne; Iman, Rizani Putri; Brazilek, Rose J.; Abidin, Nurul A. Zainal; Chicanne, Gaëtan; Séverin, Sonia; Nicholls, Alyce J.; Wong, Connie Hoi Yee; Rinckel, Jean‐Yves; Eckly, Anita; Gachet, Christian; Nesbitt, Warwick Scott; Thompson, Phillip E.; Hamilton, Justin Raymond

doi:10.1126/scitranslmed.aar8430

Cited by 20 publications

(20 citation statements)

References 36 publications

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“…While PI3KC2α is partly refractory to inhibition by wortmannin, it can be targeted by a subset of nonselective PI3K inhibitors such as Torin 2 or PIK-90 and its derivatives 4 , 28 , 30 that are promiscuous with respect to their cellular activities. We therefore reasoned that a distinct chemical scaffold may be required to selectively target PI3KC2α function.…”

Section: Resultsmentioning

confidence: 99%

Development of selective inhibitors of phosphatidylinositol 3-kinase C2α

Belabed

Kücükdisli

et al. 2022

Nat Chem Biol

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Phosphatidylinositol 3-kinase type 2α (PI3KC2α) and related class II PI3K isoforms are of increasing biomedical interest because of their crucial roles in endocytic membrane dynamics, cell division and signaling, angiogenesis, and platelet morphology and function. Herein we report the development and characterization of PhosphatidylInositol Three-kinase Class twO INhibitors (PITCOINs), potent and highly selective small-molecule inhibitors of PI3KC2α catalytic activity. PITCOIN compounds exhibit strong selectivity toward PI3KC2α due to their unique mode of interaction with the ATP-binding site of the enzyme. We demonstrate that acute inhibition of PI3KC2α-mediated synthesis of phosphatidylinositol 3-phosphates by PITCOINs impairs endocytic membrane dynamics and membrane remodeling during platelet-dependent thrombus formation. PITCOINs are potent and selective cell-permeable inhibitors of PI3KC2α function with potential biomedical applications ranging from thrombosis to diabetes and cancer.

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Section: Resultsmentioning

confidence: 99%

Development of selective inhibitors of phosphatidylinositol 3-kinase C2α

Belabed

Kücükdisli

et al. 2022

Nat Chem Biol

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“…However, a lack of selectivity for class II keeps these options far from being effective at specifically targeting class II PI3K in any pathological process. Interestingly, a subsequent study claimed the discovery of a PIK3-C2α-selective inhibitory molecule, MIPS-21335, suggesting a potential new therapeutic anti-thrombotic approach based on class II PI3K-selective targeting [ 161 ].…”

Section: Rationale For Targeting Class II Pi3k In Breast Cancermentioning

confidence: 99%

Targeting PI3K/AKT/mTOR Signaling Pathway in Breast Cancer

Prever

Hirsch

et al. 2021

Cancers

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Breast cancer is the most frequently diagnosed cancer and the primary cause of cancer death in women worldwide. Although early diagnosis and cancer growth inhibition has significantly improved breast cancer survival rate over the years, there is a current need to develop more effective systemic treatments to prevent metastasis. One of the most commonly altered pathways driving breast cancer cell growth, survival, and motility is the PI3K/AKT/mTOR signaling cascade. In the past 30 years, a great surge of inhibitors targeting these key players has been developed at a rapid pace, leading to effective preclinical studies for cancer therapeutics. However, the central role of PI3K/AKT/mTOR signaling varies among diverse biological processes, suggesting the need for more specific and sophisticated strategies for their use in cancer therapy. In this review, we provide a perspective on the role of the PI3K signaling pathway and the most recently developed PI3K-targeting breast cancer therapies.

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“…Briefly, isolated platelets were adjusted to a concentration of 3 x 10 8 /mL and subsequently stimulated with different thrombin concentrations (0.01-1 U/mL). The plate was analyzed in a plate reader of Infinite F-50 plates (TECAN) with a 405 nm excitation filter for 20 minutes (10 cycles with 1 minute of agitation between each cycle) ( 25 ).…”

Section: Methodsmentioning

confidence: 99%

Neutrophil Extracellular Trap Targeting Protects Against Ischemic Damage After Fibrin-Rich Thrombotic Stroke Despite Non-Reperfusion

et al. 2022

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Stroke is one of the most prevalent diseases worldwide caused primarily by a thrombotic vascular occlusion that leads to cell death. To date, t-PA (tissue-type plasminogen activator) is the only thrombolytic therapy approved which targets fibrin as the main component of ischemic stroke thrombi. However, due to its highly restrictive criteria, t-PA is only administrated to less than 10% of all stroke patients. Furthermore, the research in neuroprotective agents has been extensive with no translational results from medical research to clinical practice up to now. Since we first described the key role of NETs (Neutrophil Extracellular Traps) in platelet-rich thrombosis, we asked, first, whether NETs participate in fibrin-rich thrombosis and, second, if NETs modulation could prevent neurological damage after stroke. To this goal, we have used the thromboembolic in situ stroke model which produces fibrin-rich thrombotic occlusion, and the permanent occlusion of the middle cerebral artery by ligature. Our results demonstrate that NETs do not have a predominant role in fibrin-rich thrombosis and, therefore, DNase-I lacks lytic effects on fibrin-rich thrombosis. Importantly, we have also found that NETs exert a deleterious effect in the acute phase of stroke in a platelet-TLR4 dependent manner and, subsequently, that its pharmacological modulation has a neuroprotective effect. Therefore, our data strongly support that the pharmacological modulation of NETs in the acute phase of stroke, could be a promising strategy to repair the brain damage in ischemic disease, independently of the type of thrombosis involved.

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Disrupting the platelet internal membrane via PI3KC2α inhibition impairs thrombosis independently of canonical platelet activation

Cited by 20 publications

References 36 publications

Development of selective inhibitors of phosphatidylinositol 3-kinase C2α

Development of selective inhibitors of phosphatidylinositol 3-kinase C2α

Targeting PI3K/AKT/mTOR Signaling Pathway in Breast Cancer

Neutrophil Extracellular Trap Targeting Protects Against Ischemic Damage After Fibrin-Rich Thrombotic Stroke Despite Non-Reperfusion

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