Small Molecule Protein Assembly Modulators with Pan-Cancer Therapeutic Efficacy

Lingappa, Anuradha F.; Akintunde, Olayemi; Ewald, Connie; Froehlich, Markus; Ziari, Niloufar; Yu, Shao Feng; Michon, Maya; Mallesh, Suguna; Lin, Jim Jung‐Ching; Kitaygorodskyy, Anatoliy; Solas, Dennis; Reed, Jonathan C.; Lingappa, Jaisri R.; Mueller-Schiffmann, Andreas; Korth, Carsten; Prasad, M. Dharma; Ashton, Emily; Fabbri, Brad; Nalca, Aysegul; Petrouski, Emma; Dey, Debendranath; Andrews, David W.; Lingappa, Vishwanath R.

doi:10.1101/2022.09.28.509937

Cited by 3 publications

(16 citation statements)

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“…Having a drug that impinges on a biochemical pathway in a novel way is a powerful means of probing biological regulaDon, parDcularly that which depends on informaDon that does not reside simply in the sequence of the genome 12,13,14 . Thus the relevance of the compounds we have described, with their novel mechanism of acDon at allosteric sites 15,16 , and the unconvenDonal nature of the targeted mulD-protein complex (energy-dependent for formaDon, transient in existence, composed of miniscule subsets of the individual component proteins in the cell) 17,18 . These tools may provide a new understanding of the molecular basis for homeostasis.…”

Section: Introduc-onmentioning

confidence: 99%

An ALS Therapeutic Assembly Modulator Target in Peripheral Blood Mononuclear Cells: Implications for ALS Pathophysiology, Therapeutics, and Diagnostics

Yu,

Michon,

Lingappa

et al. 2024

Preprint

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Assembly modulators are a new class of allosteric site-targeted therapeutic small molecules, some of which are effective at restoring nuclear localization of TDP-43 in ALS cellular models, and display efficacy in a variety of ALS animal models. One of these compounds has been shown to target a small subfraction of protein disulfide isomerase, a known allosteric modulator implicated in ALS pathophysiology, within a novel, transient, and energy-dependent multi-protein complex that includes other important members of the ALS interactome, such as TDP-43, RanGTPase, and selective autophagy receptor p62/SQSTM1. Building on earlier literature suggesting PBMC dysfunction in ALS, we demonstrate here that a similar multi-protein complex drug target is present in PBMCs with signature alterations in PBMCs from ALS patients compared to PBMCs from healthy individuals. ALS-associated changes in the drug target include increased RanGTPase and MMP9, diminished p62/SQSTM1, and most distinctively, appearance of a 17kDa post-translationally modified form of RanGTPase. Many of these changes are not readily apparent from analysis of whole cell extracts, as a number of the proteins present in the target multi-protein complex, including RanGTPase, comprise a miniscule percent of their total in cell extracts. A small subset of each of these proteins appear to come together in a transient, energy-dependent fashion, to form the drug target. Furthermore, whole blood from ALS patients shows a distinctive degradation of RanGTPase not observed in blood from healthy individuals, which appears to be rescued by treatment with either of two structurally unrelated ALS-active assembly modulators. Our findings are consistent with the hypothesis that ALS is fundamentally a disorder of homeostasis that can be both detected and treated by assembly modulators.

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Section: Introduc-onmentioning

confidence: 99%

An ALS Therapeutic Assembly Modulator Target in Peripheral Blood Mononuclear Cells: Implications for ALS Pathophysiology, Therapeutics, and Diagnostics

Yu,

Michon,

Lingappa

et al. 2024

Preprint

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“…We utilized cell-free protein synthesis and assembly (CFPSA) systems to define a catalyzed assembly pathway for viral capsid formation (33,34). That system was then adapted into a moderate throughput drug screen to identify small molecules that block formation of viral capsids (29,30,35,36).…”

Section: Introductionmentioning

confidence: 99%

“…We screened a 150,000 compound library for small molecules with protein assembly modulating properties with respect to capsid formation for each of the viral families causing significant human disease, identifying a small numbers of hit compounds for each (27). These "protein assembly modulator" compounds were validated against infectious viruses (29,30,(35)(36)(37). Subsequently, they were tested in cellular and animal models for nonviral disease, with success (35,37).…”

Section: Introductionmentioning

confidence: 99%

“…These "protein assembly modulator" compounds were validated against infectious viruses (29,30,(35)(36)(37). Subsequently, they were tested in cellular and animal models for nonviral disease, with success (35,37). Data from the application of assembly modulation to oncology indicates that defects in protein assembly are points of overlap in the molecular-level departures from homeostasis that drive progression of both viral and neoplastic disease (35).…”

Section: Introductionmentioning

confidence: 99%

“…Subsequently, they were tested in cellular and animal models for nonviral disease, with success (35,37). Data from the application of assembly modulation to oncology indicates that defects in protein assembly are points of overlap in the molecular-level departures from homeostasis that drive progression of both viral and neoplastic disease (35). Treatment with assembly modulators appears to change the composition of particular multi-protein complexes which are comprised of a number of proteins implicated in pathogenesis of the disease, and others implicated in restoration of homeostasis, including through autophagy (35,36).…”

Section: Introductionmentioning

confidence: 99%

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Protein Assembly Modulation: A New Approach to ALS Therapeutics

Shao¹,

Paulvannan²,

Solas³

et al. 2023

Preprint

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Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease with a complex, multifactorial pathophysiology, most commonly manifest as loss of motor neurons. We introduce a new mechanism of ALS pathogenesis via a novel drug-like small molecule series that targets protein disulfide isomerase (PDI) within a previously unappreciated transient and energy-dependent multi-protein complex. This novel drug was found to have activity in cellular models for both familial and sporadic ALS, as well as in transgenic worms, flies, and mice bearing a diversity of human genes with ALS-associated mutations. These compounds were initially identified as modulators of human immunodeficiency virus (HIV) capsid assembly in cell-free protein synthesis and assembly (CFPSA) systems, with demonstrated antiviral activity in cell culture. Their advancement as ALS-therapeutics, and the subsequent separation of activity against HIV and ALS in chemical subseries through structure-activity-relationship optimization, may provide insights into the molecular mechanisms governing pathophysiology of disordered homeostasis relevant to ALS.

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