Discovery of boronic acid-based potent activators of tumor pyruvate kinase M2 and development of gastroretentive nanoformulation for oral dosing

Patle, Rajkumar; Shinde, Shital; Patel, Sagarkumar; Maheshwari, Rahul; Jariyal, Heena; Srivastava, Akshay; Chauhan, Neelam; Globisch, Christoph; Jain, Alok; Tekade, Rakesh K.; Shard, Amit

doi:10.1016/j.bmcl.2021.128062

Cited by 10 publications

(2 citation statements)

References 66 publications

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“…Recently, Patle et al reported the design and synthesis of PKM2 activators based on boronic acids based on the fact that boronic acid-based drugs are electrophilic and potent anticancer agents that improve the bioavailability issues . All the compounds showed cancer cell cytotoxicity at 80 nM.…”

Section: Pkm2 Activators Derived From Small Moleculesmentioning

confidence: 99%

A Perspective on Medicinal Chemistry Approaches for Targeting Pyruvate Kinase M2

et al. 2021

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The allosteric regulation of pyruvate kinase M2 (PKM2) affects the switching of the PKM2 protein between the high-activity and low-activity states that allow ATP and lactate production, respectively. PKM2, in its low catalytic state (dimeric form), is chiefly active in metabolically energetic cells, including cancer cells. More recently, PKM2 has emerged as an attractive target due to its role in metabolic dysfunction and other interrelated conditions. PKM2 (dimer) activity can be inhibited by modulating PKM2 dimer−tetramer dynamics using either PKM2 inhibitors that bind at the ATP binding active site of PKM2 (dimer) or PKM2 activators that bind at the allosteric site of PKM2, thus activating PKM2 from the dimer formation to the tetrameric formation. The present perspective focuses on medicinal chemistry approaches to design and discover PKM2 inhibitors and activators and further provides a scope for the future design of compounds targeting PKM2 with better efficacy and selectivity.

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Section: Pkm2 Activators Derived From Small Moleculesmentioning

confidence: 99%

A Perspective on Medicinal Chemistry Approaches for Targeting Pyruvate Kinase M2

et al. 2021

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“…PtNPs on whose surface an agent with antitumor activity has been immobilized may exhibit higher catalytic efficiency in destroying cancer cells than pure PtNPs 12 . Phosphonic acids of phenylboronic acid (PBA) and its derivatives are a promising class of candidates for inhibiting actively migrating tumor cells without affecting normal cells (e.g., human prostate and breast cancer), 14 activating pyruvate kinase M2 (PKM2), which is critical for tumorigenesis, 15 inhibiting arginase to enhance anti‐tumor immune responses, 16 etc. PBA is a boronic acid (BA) with a phenyl ring and two hydroxyl groups attached to the sp 2 hybridized boron atom.…”

Section: Introductionmentioning

confidence: 99%

Homogeneous Pt nanostructures surface functionalized with phenylboronic acid phosphonic acid derivatives as potential biochemical nanosensors and drugs: SERS and TERS studies

2023

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Here, surface-enhanced Raman scattering (SERS) and tip-enhanced Raman scattering (TERS) were used to characterize the selective adsorption of N-substituted 4-[(NH-R) (phosphono)-S-methyl]phenylboronic acids on the surface of platinum nanoparticles (PtNPs) from an aqueous solution and from air. The nature of the interaction of the studied compounds with the PtNPs/H 2 O and PtNPs/air interfaces was discussed and compared. For this purpose, 4-[(N-anilino)(phosphono)-S-methyl]phenylboronic acid (1-PBA-PA) and its two analogs (2-PBA-PA and bis{1-PBA-PA}) as well as the PtNPs were synthesized in surfactant/ion-free solution via a synthetic route that allows control of the size and morphology of the NPs. The positively charged PtNPs with a size of $12 nm were characterized by ultraviolet-visible spectroscopy (UV-Vis), dynamic light scattering (DLS), scanning electron microscopy (SEM), and X-ray powder diffraction (XRD).phenylboronic acid phosphonic acid (PBA-PA), platinum nanoparticles (PtNPs), surfaceenhanced Raman scattering (SERS), tip-enhanced Raman scattering (TERS) | INTRODUCTIONPlatinum-based (Pt) drugs are widely used to treat human cancers. [1][2][3] However, their clinical use is limited by side effects such as lack of selectivity, drug resistance, cytopenias, asthenia, anaphylaxis, and high systemic toxicity (ototoxicity, hepatotoxicity, and cardiotoxicity), as well as congenital or acquired treatment resistance. 4,5 Therefore, great efforts have been put into the search for new platinum compounds (hindered, trans-configured, or multinuclear complexes, monofunctional platinum drugs, complexes with biologically active ligands, and platinum(IV) prodrugs) with anticancer properties, but they have not found clinical application. 6-10 However, thanks to the advances in nanotechnology and the great interest in the use of metallic nanoparticles (NPs) in the development and design of highly sensitive and specific biochemical nanosensors and drugs, PtNP-based systems show promise for cancer therapies (photodynamic, chemodynamic, photothermal, radiosensitizing, etc.). [11][12][13] PtNPs on whose surface an agent with antitumor activity has been immobilized may exhibit higher catalytic efficiency in destroying cancer cells than pure PtNPs. 12 Phosphonic acids of phenylboronic acid (PBA) and its derivatives are a promising class of candidates for inhibiting actively migrating tumor cells without affecting normal cells (e.g., human prostate and breast cancer), 14 activating pyruvate kinase M2 (PKM2), which is critical for tumorigenesis, 15 inhibiting arginase to enhance anti-tumor immune responses, 16 etc. PBA is a boronic acid (BA) with a phenyl ring and two hydroxyl groups attached to the sp 2

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Boronic acid derivative activates pyruvate kinase M2 indispensable for redox metabolism in oral cancer cells

Rihan

Nalla

Dharavath

et al. 2022

Bioorganic & Medicinal Chemistry Letters

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Discovery of boronic acid-based potent activators of tumor pyruvate kinase M2 and development of gastroretentive nanoformulation for oral dosing

Cited by 10 publications

References 66 publications

A Perspective on Medicinal Chemistry Approaches for Targeting Pyruvate Kinase M2

A Perspective on Medicinal Chemistry Approaches for Targeting Pyruvate Kinase M2

Homogeneous Pt nanostructures surface functionalized with phenylboronic acid phosphonic acid derivatives as potential biochemical nanosensors and drugs: SERS and TERS studies

Boronic acid derivative activates pyruvate kinase M2 indispensable for redox metabolism in oral cancer cells

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