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1.
Drug Metab Dispos ; 51(11): 1536-1546, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37643880

ABSTRACT

RGLS4326 is a short oligonucleotide inhibitor of microRNA-17 (miR-17) that preferentially distributes to the kidney and displaces miR-17 from translationally active polysomes. Here, we present pharmacokinetics and absorption, distribution, metabolism, and excretion properties of RGLS4326 from mice and monkeys. RGLS4326 was absorbed rapidly after subcutaneous administration, distributed extensively to the kidney and liver, with preferential distribution to the kidney, and cleared rapidly from plasma by tissue uptake and renal excretion. Plasma exposure increased in a dose-proportional manner with no notable accumulation after repeat doses. Plasma protein binding of RGLS4326 across all species tested was between 79% and 96%. RGLS4326 predominantly distributed to the kidney with a long half-life (t1/2; t1/2 ranged from 8-11 days) and no marked (≤twofold) accumulation in kidney and liver after repeat doses. RGLS4326 was minimally metabolized by nucleases, not cytochrome P450 (P450) isozymes, across species and underwent sequential hydrolysis from both 3' and 5' ends to produce chain-shortened metabolites. There were no human unique metabolites observed. Renal excretion was the major route of elimination of RGLS4326, and a significant fraction (50%-79%) of the dose was recovered intact in the urine of mice and monkeys across all dose levels. RGLS4326 is not a substrate, inhibitor, or inducer of P450 isozymes, and it is not a substrate or inhibitor of uptake and most efflux transporters. Thus, RGLS4326 exhibits low potential of mediating drug-drug interactions involving P450 isozymes and drug transporters. SIGNIFICANCE STATEMENT: Pharmacokinetics (PK) and absorption, distribution, metabolism, and excretion (ADME) properties of RGLS4326 were characterized in vivo and in vitro. RGLS4326 shows similar PK and ADME properties across mice and monkeys in vivo and across human and animal matrices in vitro. Subcutaneous administration results in preferential exposure of RGLS4326 to the intended target organ (kidney) to drive maximum target engagement. These studies support the interpretation of toxicology and efficacy studies and help characterize the disposition of RGLS4326 in humans.

2.
Nat Commun ; 13(1): 4765, 2022 08 15.
Article in English | MEDLINE | ID: mdl-35965273

ABSTRACT

Autosomal dominant polycystic kidney disease (ADPKD), among the most common human genetic conditions and a frequent etiology of kidney failure, is primarily caused by heterozygous PKD1 mutations. Kidney cyst formation occurs when PKD1 dosage falls below a critical threshold. However, no framework exists to harness the remaining allele or reverse PKD1 decline. Here, we show that mRNAs produced by the noninactivated PKD1 allele are repressed via their 3'-UTR miR-17 binding element. Eliminating this motif (Pkd1∆17) improves mRNA stability, raises Polycystin-1 levels, and alleviates cyst growth in cellular, ex vivo, and mouse PKD models. Remarkably, Pkd2 is also inhibited via its 3'-UTR miR-17 motif, and Pkd2∆17-induced Polycystin-2 derepression retards cyst growth in Pkd1-mutant models. Moreover, acutely blocking Pkd1/2 cis-inhibition, including after cyst onset, attenuates murine PKD. Finally, modeling PKD1∆17 or PKD2∆17 alleles in patient-derived primary ADPKD cultures leads to smaller cysts, reduced proliferation, lower pCreb1 expression, and improved mitochondrial membrane potential. Thus, evading 3'-UTR cis-interference and enhancing PKD1/2 mRNA translation is a potentially mutation-agnostic ADPKD-arresting approach.


Subject(s)
Cysts , MicroRNAs , Polycystic Kidney, Autosomal Dominant , Protein Kinase C/metabolism , TRPP Cation Channels/metabolism , Animals , Cysts/genetics , Disease Models, Animal , Humans , Mice , MicroRNAs/genetics , Polycystic Kidney, Autosomal Dominant/genetics , RNA, Messenger/genetics , TRPP Cation Channels/genetics
3.
Nat Commun ; 10(1): 4148, 2019 09 12.
Article in English | MEDLINE | ID: mdl-31515477

ABSTRACT

Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations in either PKD1 or PKD2 genes, is one of the most common human monogenetic disorders and the leading genetic cause of end-stage renal disease. Unfortunately, treatment options for ADPKD are limited. Here we report the discovery and characterization of RGLS4326, a first-in-class, short oligonucleotide inhibitor of microRNA-17 (miR-17), as a potential treatment for ADPKD. RGLS4326 is discovered by screening a chemically diverse and rationally designed library of anti-miR-17 oligonucleotides for optimal pharmaceutical properties. RGLS4326 preferentially distributes to kidney and collecting duct-derived cysts, displaces miR-17 from translationally active polysomes, and de-represses multiple miR-17 mRNA targets including Pkd1 and Pkd2. Importantly, RGLS4326 demonstrates a favorable preclinical safety profile and attenuates cyst growth in human in vitro ADPKD models and multiple PKD mouse models after subcutaneous administration. The preclinical characteristics of RGLS4326 support its clinical development as a disease-modifying treatment for ADPKD.


Subject(s)
MicroRNAs/antagonists & inhibitors , Oligonucleotides/therapeutic use , Polycystic Kidney Diseases/drug therapy , Polycystic Kidney Diseases/genetics , Animals , Base Sequence , Cell Proliferation/drug effects , Disease Models, Animal , Gene Regulatory Networks/drug effects , HeLa Cells , Hematopoiesis/drug effects , Humans , Kidney Tubules/pathology , Macaca fascicularis , Male , Mice, Inbred C57BL , MicroRNAs/genetics , Oligonucleotides/pharmacokinetics , Oligonucleotides/pharmacology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Tissue Distribution/drug effects
4.
Mol Cancer Ther ; 16(5): 905-913, 2017 05.
Article in English | MEDLINE | ID: mdl-28167506

ABSTRACT

Hepatocellular carcinoma (HCC) is one of the most common human malignancies with poor prognosis and urgent unmet medical need. Aberrant expression of multiple members of the miR-17 family are frequently observed in HCC, and their overexpression promotes tumorigenic properties of HCC cells. However, whether pharmacologic inhibition of the miR-17 family inhibits HCC growth remains unknown. In this study, we validated that the miR-17 family was upregulated in a subset of HCC tumors and cell lines and its inhibition by a tough decoy inhibitor suppressed the growth of Hep3B and HepG2 cells, which overexpress the miR-17 family. Furthermore, inhibition of the miR-17 family led to a global derepression of direct targets of the family in all three HCC cell lines tested. Pathway analysis of the deregulated genes indicated that the genes associated with TGFß signaling pathway were highly enriched in Hep3B and HepG2 cells. A miR-17 family target gene signature was established and used to identify RL01-17(5), a lipid nanoparticle encapsulating a potent anti-miR-17 family oligonucleotide. To address whether pharmacologic modulation of the miR-17 family can inhibit HCC growth, RL01-17(5) was systemically administrated to orthotopic Hep3B xenografts. Suppression of Hep3B tumor growth in vivo was observed and tumor growth inhibition correlated with induction of miR-17 family target genes. Together, this study provides proof-of-concept for targeting the miR-17 family in HCC therapy. Mol Cancer Ther; 16(5); 905-13. ©2017 AACR.


Subject(s)
Antagomirs/administration & dosage , Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/drug therapy , MicroRNAs/genetics , Animals , Antagomirs/genetics , Carcinogenesis/drug effects , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , Gene Expression Regulation, Neoplastic/drug effects , Hep G2 Cells , Humans , Lipids/administration & dosage , Lipids/chemistry , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Mice , MicroRNAs/antagonists & inhibitors , MicroRNAs/chemistry , Nanoparticles/administration & dosage , Nanoparticles/chemistry , Oligonucleotides/administration & dosage , Oligonucleotides/genetics , Xenograft Model Antitumor Assays
5.
Nat Commun ; 8: 14395, 2017 02 16.
Article in English | MEDLINE | ID: mdl-28205547

ABSTRACT

Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent genetic cause of renal failure. Here we identify miR-17 as a target for the treatment of ADPKD. We report that miR-17 is induced in kidney cysts of mouse and human ADPKD. Genetic deletion of the miR-17∼92 cluster inhibits cyst proliferation and PKD progression in four orthologous, including two long-lived, mouse models of ADPKD. Anti-miR-17 treatment attenuates cyst growth in short-term and long-term PKD mouse models. miR-17 inhibition also suppresses proliferation and cyst growth of primary ADPKD cysts cultures derived from multiple human donors. Mechanistically, c-Myc upregulates miR-17∼92 in cystic kidneys, which in turn aggravates cyst growth by inhibiting oxidative phosphorylation and stimulating proliferation through direct repression of Pparα. Thus, miR-17 family is a promising drug target for ADPKD, and miR-17-mediated inhibition of mitochondrial metabolism represents a potential new mechanism for ADPKD progression.


Subject(s)
MicroRNAs/metabolism , Mitochondria/metabolism , Polycystic Kidney, Autosomal Dominant/metabolism , Animals , Cell Proliferation/physiology , Disease Models, Animal , Disease Progression , Female , Gene Deletion , Humans , Male , Mice , Mice, Knockout , MicroRNAs/genetics , Phosphorylation , Polycystic Kidney, Autosomal Dominant/genetics , Polycystic Kidney, Autosomal Dominant/pathology , Polycystic Kidney, Autosomal Dominant/therapy , Up-Regulation
6.
J Med Chem ; 56(20): 7788-803, 2013 Oct 24.
Article in English | MEDLINE | ID: mdl-24093940

ABSTRACT

The IAPs are key regulators of the apoptotic pathways and are commonly overexpressed in many cancer cells. IAPs contain one to three BIR domains that are crucial for their inhibitory function. The pro-survival properties of XIAP come from binding of the BIR domains to the pro-apoptotic caspases. The BIR3 domain of XIAP binds and inhibits caspase 9, while the BIR2 domain binds and inhibits the terminal caspases 3 and 7. While XIAP BIR3 inhibitors have previously been reported, they also inhibit cIAP1/2 and promote the release of TNFα, potentially limiting their therapeutic utility. This paper will focus on the optimization of selective XIAP BIR2 inhibitors leading to the discovery of highly potent benzodiazepinone 36 (IC50 = 45 nM), which has high levels of selectivity over XIAP BIR3 and cIAP1 BIR2/3 and shows efficacy in a xenograft pharmacodynamic model monitoring caspase activity while not promoting the release of TNFα in vitro.


Subject(s)
Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/pharmacology , Inhibitor of Apoptosis Proteins/antagonists & inhibitors , X-Linked Inhibitor of Apoptosis Protein/antagonists & inhibitors , Alanine/analogs & derivatives , Alanine/chemical synthesis , Alanine/pharmacokinetics , Alanine/pharmacology , Animals , Apoptosis/drug effects , Benzodiazepinones/chemical synthesis , Benzodiazepinones/pharmacokinetics , Benzodiazepinones/pharmacology , Blotting, Western , Caspase 3/metabolism , Caspase 7/metabolism , Cell Line, Tumor , Cell Survival/drug effects , Crystallography, X-Ray , Female , Heterocyclic Compounds/pharmacokinetics , Humans , Inhibitor of Apoptosis Proteins/chemistry , Inhibitor of Apoptosis Proteins/metabolism , Mice , Mice, Nude , Models, Chemical , Models, Molecular , Molecular Structure , Protein Structure, Tertiary , Ubiquitin-Protein Ligases , X-Linked Inhibitor of Apoptosis Protein/chemistry , X-Linked Inhibitor of Apoptosis Protein/metabolism , Xenograft Model Antitumor Assays
7.
Clin Cancer Res ; 17(23): 7313-23, 2011 Dec 01.
Article in English | MEDLINE | ID: mdl-21903769

ABSTRACT

PURPOSE: The clinical success of the first-in-class proteasome inhibitor bortezomib (VELCADE) has validated the proteasome as a therapeutic target for treating human cancers. MLN9708 is an investigational proteasome inhibitor that, compared with bortezomib, has improved pharmacokinetics, pharmacodynamics, and antitumor activity in preclinical studies. Here, we focused on evaluating the in vivo activity of MLN2238 (the biologically active form of MLN9708) in a variety of mouse models of hematologic malignancies, including tumor xenograft models derived from a human lymphoma cell line and primary human lymphoma tissue, and genetically engineered mouse (GEM) models of plasma cell malignancies (PCM). EXPERIMENTAL DESIGN: Both cell line-derived OCI-Ly10 and primary human lymphoma-derived PHTX22L xenograft models of diffuse large B-cell lymphoma were used to evaluate the pharmacodynamics and antitumor effects of MLN2238 and bortezomib. The iMyc(Cα)/Bcl-X(L) GEM model was used to assess their effects on de novo PCM and overall survival. The newly developed DP54-Luc-disseminated model of iMyc(Cα)/Bcl-X(L) was used to determine antitumor activity and effects on osteolytic bone disease. RESULTS: MLN2238 has an improved pharmacodynamic profile and antitumor activity compared with bortezomib in both OCI-Ly10 and PHTX22L models. Although both MLN2238 and bortezomib prolonged overall survival, reduced splenomegaly, and attenuated IgG2a levels in the iMyc(Cα)/Bcl-X(L) GEM model, only MLN2238 alleviated osteolytic bone disease in the DP54-Luc model. CONCLUSIONS: Our results clearly showed the antitumor activity of MLN2238 in a variety of mouse models of B-cell lymphoma and PCM, supporting its clinical development. MLN9708 is being evaluated in multiple phase I and I/II trials.


Subject(s)
Antineoplastic Agents/pharmacology , Boron Compounds/pharmacology , Glycine/analogs & derivatives , Lymphoma, B-Cell/drug therapy , Neoplasms, Plasma Cell/drug therapy , Animals , Antineoplastic Agents/pharmacokinetics , Boron Compounds/administration & dosage , Boron Compounds/pharmacokinetics , Boronic Acids/pharmacokinetics , Boronic Acids/pharmacology , Bortezomib , Cell Line, Tumor , Glycine/administration & dosage , Glycine/pharmacokinetics , Glycine/pharmacology , Humans , Lymphoma, B-Cell/metabolism , Mice , Mice, Inbred C57BL , Mice, Inbred NOD , Mice, SCID , Mice, Transgenic , Neoplasms, Plasma Cell/metabolism , Osteolysis/drug therapy , Osteolysis/etiology , Protease Inhibitors/pharmacology , Proteasome Inhibitors , Pyrazines/pharmacokinetics , Pyrazines/pharmacology , Xenograft Model Antitumor Assays
8.
Cancer Res ; 70(5): 1970-80, 2010 Mar 01.
Article in English | MEDLINE | ID: mdl-20160034

ABSTRACT

The proteasome was validated as an oncology target following the clinical success of VELCADE (bortezomib) for injection for the treatment of multiple myeloma and recurring mantle cell lymphoma. Consequently, several groups are pursuing the development of additional small-molecule proteasome inhibitors for both hematologic and solid tumor indications. Here, we describe MLN9708, a selective, orally bioavailable, second-generation proteasome inhibitor that is in phase I clinical development. MLN9708 has a shorter proteasome dissociation half-life and improved pharmacokinetics, pharmacodynamics, and antitumor activity compared with bortezomib. MLN9708 has a larger blood volume distribution at steady state, and analysis of 20S proteasome inhibition and markers of the unfolded protein response confirmed that MLN9708 has greater pharmacodynamic effects in tissues than bortezomib. MLN9708 showed activity in both solid tumor and hematologic preclinical xenograft models, and we found a correlation between greater pharmacodynamic responses and improved antitumor activity. Moreover, antitumor activity was shown via multiple dosing routes, including oral gavage. Taken together, these data support the clinical development of MLN9708 for both hematologic and solid tumor indications.


Subject(s)
Boron Compounds/pharmacology , Cysteine Proteinase Inhibitors/pharmacology , Glycine/analogs & derivatives , Neoplasms/drug therapy , Neoplasms/enzymology , Proteasome Inhibitors , Animals , Boron Compounds/pharmacokinetics , Boronic Acids/pharmacology , Bortezomib , Cysteine Proteinase Inhibitors/pharmacokinetics , Drug Screening Assays, Antitumor , Female , Glycine/pharmacokinetics , Glycine/pharmacology , HCT116 Cells , HT29 Cells , Humans , Lymphoma/drug therapy , Lymphoma/enzymology , Mice , Mice, SCID , Proteasome Endopeptidase Complex/blood , Pyrazines/pharmacology , Xenograft Model Antitumor Assays
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