Laurent Meijer

Laurent Meijer
Perha Pharmaceuticals

PhD
Chairman & CSO of ManRos Therapeutics & Perha Pharmaceuticals

About

580
Publications
106,918
Reads
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34,237
Citations
Introduction
Perha Pharmaceuticals is a biotech company identifying, optimizing, characterizing innovative, low molecular weight kinase inhibitors and developing them up to proof-of-concept in man. Perha Pharma focuses its research on two main diseases: hearing loss (HL) induced by ototoxic products and cognitive disorders associated with Down syndrome (DS) and Alzheimer’s disease.
Additional affiliations
July 2019 - present
Perha Pharmaceuticals
Position
  • CEO
Description
  • A small biotech company developing kinase inhibitors for the treatment of (1) hearing loss induced by ototoxic compounds or acoustic trauma, (2) cognitive deficits associated with Down syndrome and Alzheimer's disease
June 2011 - present
ManRos Therapeutics
ManRos Therapeutics
Position
  • CEO
Description
  • A small biotech company developing protein kinase inhibitors for the treatment of cystic fibrosis.
August 2001 - August 2004
The Rockefeller University
Position
  • Professor
Education
October 1978 - June 1983
Sorbonne Université
Field of study
  • Cell biology
September 1976 - July 1978
Université de Lille
Field of study
  • Endocrinology & cell biology

Publications

Publications (580)
Article
Full-text available
Metabolic dysfunction mutations can impair energy sensing and cause cancer. Loss of function of the mitochondrial tricarboxylic acid (TCA) cycle enzyme subunit succinate dehydrogenase B (SDHB) results in various forms of cancer typified by pheochromocytoma (PC). Here we delineate a signaling cascade where the loss of SDHB induces the Warburg effect...
Preprint
Full-text available
Metabolic dysfunction mutations can impair energy sensing and cause cancer. Loss of function of mitochondrial TCA cycle enzyme, succinate dehydrogenase B (SDHB) results in various forms of cancer typified by pheochromocytoma (PC). Here we delineate a signaling cascade where the loss of SDHB induces the Warburg effect in PC tumors, triggers dysregul...
Article
Full-text available
Background: Alzheimer's disease (AD) is a continuum of events beginning with an increase in brain soluble Aβ42 followed by the appearance of hyperphosphorylated tau (P-tau, asymptomatic stage). Mild Cognitive Impairment (MCI) then appears (prodromal stage). However, the individual contribution of these two soluble proteins in the onset of the firs...
Article
Background The orally available kinase inhibitor R-roscovitine has undergone clinical trials against various cancers and is currently under clinical evaluation against Cushing disease and rheumatoid arthritis. Roscovitine displays biological properties suggesting potential benefits in CF: it partially corrects F508del-CFTR trafficking, stimulates t...
Article
Full-text available
Here, we report on the synthesis of libraries of new 5-arylidene-2-thioxo-1,3-thiazolidin-4-ones 3 (twenty-two compounds) and new 2-amino-5-arylidene-1,3-thiazol-4(5H)-ones 5 (twenty-four compounds) with stereo controlled Z-geometry under microwave irradiation. The 46 designed final compounds were tested in order to determine their activity against...
Article
Full-text available
Dual-specificity tyrosine phosphorylation-regulated kinases (DYRK1A, 1B, 2-4) and cdc2-like kinases (CLK1-4) belong to the CMGC group of serine/threonine kinases. These protein kinases are involved in multiple cellular functions, including intracellular signaling, mRNA splicing, chromatin transcription, DNA damage repair, cell survival, cell cycle...
Article
Full-text available
Salivary gland cancers (SGCs) are rare yet aggressive malignancies with significant histological heterogeneity, which has made prediction of prognosis and development of targeted therapies challenging. In majority of patients, local recurrence and/or distant metastasis are common and systemic treatments have minimal impact on survival. Therefore, i...
Article
Full-text available
Cystic fibrosis (CF) is characterized by chronic bacterial infections and heightened inflammation. Widespread ineffective antibiotic use has led to increased isolation of drug resistant bacterial strains from respiratory samples. (R)-roscovitine (Seliciclib) is a unique drug that has many benefits in CF studies. We sought to determine roscovitine’s...
Article
Full-text available
Roscovitine (Seliciclib), a new protein kinase inhibitor, was administered orally to adult patients with cystic fibrosis for the first time in the ROSCO-CF trial, a dose-escalation, phase IIa, randomized, controlled trial. Extensive pharmacokinetic sampling was performed up to 12 h after the first oral dose. Roscovitine and its main metabolite M3 w...
Article
Full-text available
Autosomal dominant polycystic kidney disease (ADPKD) is the most common inheritable cause of end stage renal disease and, as of today, only a single moderately effective treatment is available for patients. Even though ADPKD research has made huge progress over the last decades, the precise disease mechanisms remain elusive. However, a wide variety...
Article
Full-text available
We previously highlighted the interest in 6,5,6-fused tricyclic analogues of 4-aminoquinazolines as kinase inhibitors in the micromolar to the nanomolar range of IC50 values. For the generation of chemical libraries, the formamide-mediated cyclization of the cyanoamidine precursors was carried out under microwave irradiation in an eco-friendly appr...
Article
Full-text available
Fipronil is an insecticide widely used for veterinary and agricultural purposes. While its insecticidal properties mostly rely on its high affinity antagonistic activity on insect γ aminobutyric acid (GABA) receptors, fipronil and its main metabolite fipronil sulfone nevertheless display non-negligible affinity for mammalian GABAA receptor. As seve...
Article
Full-text available
Neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease, are characterized by increased protein aggregation in the brain, progressive neuronal loss, increased inflammation, and neurogenesis impairment. We analyzed the effects of a new purine derivative drug, PDD005, in attenuating mechanisms involved in the pathogenesis of neurode...
Article
Full-text available
Dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs) hyperactivity has been linked to the development of a number of human malignancies. DYRK1A is the most studied family member, and the discovery of novel specific inhibitors is attracting considerable interest. The 8-cyclopropyl-2(pyridin-3-yl)thiazolo[5,4-f]quinazolin-9(8H)-one (al...
Conference Paper
Background: Pheochromocytoma (PC) is a rare Neuroendocrine (NE) tumor usually originates from adrenal gland’s chromaffin cells. These tumors are often benign but can become malignant causing excessive secretion of catecholamines leading to life threatening situation. Pro-tumorigenic role of CDK5, a proline-directed serine/threonine neuronal kinase...
Article
Full-text available
Since hyperactivity of the protein kinase DYRK1A is linked to several neurodegenerative disorders, DYRK1A inhibitors have been suggested as potential therapeutics for Down syndrome and Alzheimer’s disease. Most published inhibitors to date suffer from low selectivity against related kinases or from unfavorable physicochemical properties. In order t...
Article
Full-text available
Introduction: Neuronal p3-Alcβ peptides are generated from the precursor protein Alcadein β (Alcβ) through cleavage by α- and γ-secretases of the amyloid β (Aβ) protein precursor (APP). To reveal whether p3-Alcβ is involved in Alzheimer's disease (AD) contributes for the development of novel therapy and/or drug targets. Methods: We developed new...
Article
Introduction Targeting the infiltrative nature of GBMs with anti-migratory drugs as combination treatment for prevention of tumour recurrence is an attractive disease management option. One such class of drugs are the GSK-3 inhibitors 6-bromoindirubin-3′-oximes (BIO). BIO has been proposed for use in combination therapy, however, the administration...
Article
Full-text available
Thirteen nitrogen-containing molecules (1a/1b and 2–12) were isolated from the Indonesian sponge Acanthostrongylophora ingens, highlighting the richness of this organism as a source of alkaloids. Their structures were elucidated using one- and two-dimensional NMR spectroscopy and HR-ESI-MS, while the stereochemistry of the diketopiperazines was est...
Article
Full-text available
Adenosine triphosphate binding cassette transporter, subfamily B member 4 (ABCB4) is the transporter of phosphatidylcholine at the canalicular membrane of hepatocytes. ABCB4 deficiency, due to genetic variations, is responsible for progressive familial intrahepatic cholestasis type 3 (PFIC3) and other rare biliary diseases. Roscovitine is a molecul...
Article
Full-text available
Recent evidences suggest the involvement of DYRK1A (dual specificity tyrosine phosphorylation-regulated kinase 1 A) in Alzheimer’s disease (AD). Here we showed that DYRK1A undergoes a proteolytic processing in AD patients hippocampus without consequences on its kinase activity. Resulting truncated forms accumulate in astrocytes and exhibit increase...
Article
Full-text available
Traumatic brain injury (TBI) is a risk factor for a group of neurodegenerative diseases termed tauopathies, which includes Alzheimer's disease and chronic traumatic encephalopathy (CTE). Although TBI is stratified by impact severity as either mild (m), moderate or severe, mTBI is the most common and the most difficult to diagnose. Tauopathies are p...
Article
Background: Virtual screening is vital for contemporary drug discovery but striking performance fluctuations are commonly encountered, thus hampering error-free use. Results and Methodology: A conceptual framework is suggested for combining screening algorithms characterized by orthogonality (docking-scoring calculations, 3D shape similarity, 2D f...
Article
Full-text available
Efficient metal catalyzed C–H arylation of 8-alkyl-thiazolo[5,4-f]-quinazolin-9-ones was explored for SAR studies. Application of this powerful chemical tool at the last stage of the synthesis of kinase inhibitors allowed the synthesis of arrays of molecules inspired by fragment-growing studies generated by molecular modeling calculations. Among th...
Article
Full-text available
Growing evidence support the implication of DYRK1A in the development of cognitive deficits seen in Down syndrome (DS) and Alzheimer's disease (AD). We here demonstrate that pharmacological inhibition of brain DYRK1A is able to correct recognition memory deficits in three DS mouse models with increasing genetic complexity (Tg(Dyrk1a), Ts65Dn, Dp1Ye...
Article
Full-text available
Cdc2-like kinases (CLKs) represent a family of serine-threonine kinases involved in the regulation of splicing by phosphorylation of SR-proteins and other splicing factors. Although compounds acting against CLKs have been described, only a few show selectivity against dual-specificity tyrosine phosphorylation regulated-kinases (DYRKs). We here repo...
Data
Result of a docking experiment with 8c in CLK1. (PDF)
Data
Results of crystal violet assays with KuWal151. (PDF)
Data
Results from a preliminary screening for CLK1 inhibitors. (PDF)
Article
Full-text available
Cell cycle proteins are mainly expressed by dividing cells. However, it is well established that these molecules play additional non-canonical activities in several cell death contexts. Increasing evidence shows expression of cell cycle regulating proteins in post-mitotic cells, including mature neurons, following neuronal insult. Several cyclin-de...
Article
Following the discovery of (R)-roscovitine's beneficial effects in three polycystic kidney disease (PKD) mouse models, cyclin-dependent kinases (CDKs) inhibitors are investigated as potential treatments. We have used various affinity chromatography approaches to identify the molecular targets of roscovitine and its more potent analogue (S)-CR8 in h...
Article
Generation of amyloid-β peptides (Aβs) by proteolytic cleavage of the amyloid-β protein precursor (AβPP), especially increased production of Aβ42/Aβ43 over Aβ40, and their aggregation as oligomers and plaques, represent a characteristic feature of Alzheimer’s disease (AD). In familial AD (FAD), altered Aβ production originates from specific mutatio...
Article
Full-text available
Generation of amyloid β peptides (Aβs) by proteolytic cleavage of the amyloid precursor protein (AβPP), especially increased production of Aβ42/Aβ43 over Aβ40, and their aggregation as oligomers and plaques, represent a characteristic feature of Alzheimer’s disease (AD). In familial AD (FAD), altered Aβ production originates from specific mutations...
Article
Full-text available
Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a potential drug target because of its role in the development of Down syndrome and Alzheimer’s disease. The selective DYRK1A inhibitor 10-iodo-11H-indolo[3,2-c]quinoline-6-carboxylic acid (KuFal194), a large, flat and lipophilic molecule, suffers from poor water solubility,...
Article
Full-text available
A large diversity of 2-aminoimidazolone alkaloids is produced by various marine invertebrates, especially by the marine Calcareous sponges Leucetta and Clathrina. The phylogeny of these sponges and the wide scope of 2-aminoimidazolone alkaloids they produce are reviewed in this article. The origin (invertebrate cells, associated microorganisms, or...
Article
Full-text available
A compound collection of pronounced structural diversity was comprehensively screened for inhibitors of the DNA damage-related kinase CK1. The collection was evaluated in vitro. A potent and selective CK1 inhibitor was discovered and its capacity to modulate the endogenous levels of the CK1-regulated tumor suppressor p53 was demonstrated in cancer...