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3 results on '"Forbes CD"'

1. Regulated induced proximity targeting chimeras-RIPTACs-A heterobifunctional small molecule strategy for cancer selective therapies.

Author

Raina K, Forbes CD, Stronk R, Rappi JP Jr, Eastman KJ, Zaware N, Yu X, Li H, Bhardwaj A, Gerritz SW, Forgione M, Hundt A, King MP, Posner ZM, Correia AD, McGovern A, Puleo DE, Chenard R, Mousseau JJ, Vergara JI, Garvin E, Macaluso J, Martin M, Bassoli K, Jones K, Garcia M, Howard K, Yaggi M, Smith LM, Chen JM, Mayfield AB, De Leon CA, Hines J, Kayser-Bricker KJ, and Crews CM

Subjects
Humans, Neoplasms drug therapy, Neoplasms metabolism, Neoplasms pathology, Cell Proliferation drug effects, Triazoles chemistry, Triazoles pharmacology, Polo-Like Kinase 1, Protein Serine-Threonine Kinases metabolism, Protein Serine-Threonine Kinases antagonists & inhibitors, Azepines pharmacology, Azepines chemistry, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins antagonists & inhibitors, Transcription Factors metabolism, Transcription Factors antagonists & inhibitors, Indolizines chemistry, Indolizines pharmacology, Cell Line, Tumor, Bridged Bicyclo Compounds, Heterocyclic chemistry, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Ligands, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors chemical synthesis, Heterocyclic Compounds, 2-Ring pharmacology, Heterocyclic Compounds, 2-Ring chemistry, Heterocyclic Compounds, 2-Ring chemical synthesis, Nuclear Proteins metabolism, Nuclear Proteins antagonists & inhibitors, Bromodomain Containing Proteins, Cyclic N-Oxides, Pyridinium Compounds, Cell Cycle Proteins metabolism, Cell Cycle Proteins antagonists & inhibitors, Small Molecule Libraries chemistry, Small Molecule Libraries pharmacology, Small Molecule Libraries chemical synthesis, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents chemical synthesis
Abstract

We describe a protein proximity inducing therapeutic modality called Regulated Induced Proximity Targeting Chimeras or RIPTACs: heterobifunctional small molecules that elicit a stable ternary complex between a target protein (TP) selectively expressed in tumor cells and a pan-expressed protein essential for cell survival. The resulting co-operative protein-protein interaction (PPI) abrogates the function of the essential protein, thus leading to death selectively in cells expressing the TP. This approach leverages differentially expressed intracellular proteins as novel cancer targets, with the advantage of not requiring the target to be a disease driver. In this chemical biology study, we design RIPTACs that incorporate a ligand against a model TP connected via a linker to effector ligands such as JQ1 (BRD4) or BI2536 (PLK1) or CDK inhibitors such as TMX3013 or dinaciclib. RIPTACs accumulate selectively in cells expressing the HaloTag-FKBP target, form co-operative intracellular ternary complexes, and induce an anti-proliferative response in target-expressing cells., Competing Interests: Declaration of interests C.M.C. is a shareholder and consultant to Halda Therapeutics, which supports research in his laboratory., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Published
2024
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2. Regulated Induced Proximity Targeting Chimeras (RIPTACs): a Novel Heterobifunctional Small Molecule Therapeutic Strategy for Killing Cancer Cells Selectively.

Author

Raina K, Forbes CD, Stronk R, Rappi JP Jr, Eastman KJ, Gerritz SW, Yu X, Li H, Bhardwaj A, Forgione M, Hundt A, King MP, Posner ZM, Denny A, McGovern A, Puleo DE, Garvin E, Chenard R, Zaware N, Mousseau JJ, Macaluso J, Martin M, Bassoli K, Jones K, Garcia M, Howard K, Smith LM, Chen JM, De Leon CA, Hines J, Kayser-Bricker KJ, and Crews CM

Abstract

While specific cell signaling pathway inhibitors have yielded great success in oncology, directly triggering cancer cell death is one of the great drug discovery challenges facing biomedical research in the era of precision oncology. Attempts to eradicate cancer cells expressing unique target proteins, such as antibody-drug conjugates (ADCs), T-cell engaging therapies, and radiopharmaceuticals have been successful in the clinic, but they are limited by the number of targets given the inability to target intracellular proteins. More recently, heterobifunctional small molecules such as Proteolysis Targeting Chimera (PROTACs) have paved the way for protein proximity inducing therapeutic modalities. Here, we describe a proof-of-concept study using novel heterobifunctional small molecules called R egulated I nduced P roximity Ta rgeting C himeras or RIPTACs, which elicit a stable ternary complex between a target protein selectively expressed in cancer tissue and a pan-expressed protein essential for cell survival. The resulting cooperative protein:protein interaction (PPI) abrogates the function of the essential protein, thus leading to cell death selectively in cells expressing the target protein. This approach not only opens new target space by leveraging differentially expressed intracellular proteins but also has the advantage of not requiring the target to be a driver of disease. Thus, RIPTACs can address non-target mechanisms of resistance given that cell killing is driven by inactivation of the essential protein. Using the HaloTag7-FKBP model system as a target protein, we describe RIPTACs that incorporate a covalent or non-covalent target ligand connected via a linker to effector ligands such as JQ1 (BRD4), BI2536 (PLK1), or multi-CDK inhibitors such as TMX3013 or dinaciclib. We show that these RIPTACs exhibit positive co-operativity, accumulate selectively in cells expressing HaloTag7-FKBP, form stable target:RIPTAC:effector trimers in cells, and induce an anti-proliferative response in target-expressing cells. We propose that RIPTACs are a novel heterobifunctional therapeutic modality to treat cancers that are known to selectively express a specific intracellular protein., Competing Interests: Conflicts of Interest C.M.C. is a shareholder and consultant to Halda Therapeutics, which supports research in his laboratory.

Published
2023
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3. Large-scale functional LIPA variant characterization to improve birth prevalence estimates of lysosomal acid lipase deficiency.

Author

Del Angel G, Hutchinson AT, Jain NK, Forbes CD, and Reynders J

Subjects
Algorithms, Gene Expression, Genetic Association Studies, Genotype, Humans, Mutation, Phenotype, Prevalence, ROC Curve, Genetic Predisposition to Disease, Genetic Variation, Models, Genetic, Sterol Esterase genetics, Wolman Disease epidemiology, Wolman Disease genetics
Abstract

Lysosomal acid lipase (LAL) deficiency is an autosomal recessive disorder caused by LIPA gene mutations that disrupt LAL activity. We performed in vitro functional testing of 149 LIPA variants to increase the understanding of the variant effects on LAL deficiency and to improve disease prevalence estimates. Chosen variants had been reported in literature or population databases. Functional testing was done by plasmid transient transfection and LAL activity assessment. We assembled a set of 165 published LAL deficient patient genotypes to evaluate this assay's effectiveness to recapitulate genotype/phenotype relationships. Rapidly progressive LAL deficient patients showed negligible enzymatic activity (<1%), whereas patients with childhood/adult LAL deficiency typically have 1-7% average activity. We benchmarked six in silico variant effect prediction algorithms with these functional data. PolyPhen-2 was shown to have a superior area under the receiver operating curve performance. We used functional data along with Genome Aggregation Database (gnomAD) allele frequencies to estimate LAL deficiency birth prevalence, yielding a range of 3.45-5.97 cases per million births in European-ancestry populations. The low estimate only considers functionally assayed variants in gnomAD. The high estimate computes allele frequencies for variants absent in gnomAD, and uses in silico scores for unassayed variants. Prevalence estimates are lower than previously published, underscoring LAL deficiency's rarity., (© 2019 The Authors. Human Mutation Published by Wiley Periodicals, Inc.)

Published
2019
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