RESUMEN
PKMYT1 is a regulator of CDK1 phosphorylation and is a compelling therapeutic target for the treatment of certain types of DNA damage response cancers due to its established synthetic lethal relationship with CCNE1 amplification. To date, no selective inhibitors have been reported for this kinase that would allow for investigation of the pharmacological role of PKMYT1. To address this need compound 1 was identified as a weak PKMYT1 inhibitor. Introduction of a dimethylphenol increased potency on PKMYT1. These dimethylphenol analogs were found to exist as atropisomers that could be separated and profiled as single enantiomers. Structure-based drug design enabled optimization of cell-based potency. Parallel optimization of ADME properties led to the identification of potent and selective inhibitors of PKMYT1. RP-6306 inhibits CCNE1-amplified tumor cell growth in several preclinical xenograft models. The first-in-class clinical candidate RP-6306 is currently being evaluated in Phase 1 clinical trials for treatment of various solid tumors.
Asunto(s)
Neoplasias , Proteínas Tirosina Quinasas , Línea Celular Tumoral , Proliferación Celular , Humanos , Proteínas de la Membrana , Neoplasias/patología , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Serina-Treonina QuinasasRESUMEN
Amplification of the CCNE1 locus on chromosome 19q12 is prevalent in multiple tumour types, particularly in high-grade serous ovarian cancer, uterine tumours and gastro-oesophageal cancers, where high cyclin E levels are associated with genome instability, whole-genome doubling and resistance to cytotoxic and targeted therapies1-4. To uncover therapeutic targets for tumours with CCNE1 amplification, we undertook genome-scale CRISPR-Cas9-based synthetic lethality screens in cellular models of CCNE1 amplification. Here we report that increasing CCNE1 dosage engenders a vulnerability to the inhibition of the PKMYT1 kinase, a negative regulator of CDK1. To inhibit PKMYT1, we developed RP-6306, an orally bioavailable and selective inhibitor that shows single-agent activity and durable tumour regressions when combined with gemcitabine in models of CCNE1 amplification. RP-6306 treatment causes unscheduled activation of CDK1 selectively in CCNE1-overexpressing cells, promoting early mitosis in cells undergoing DNA synthesis. CCNE1 overexpression disrupts CDK1 homeostasis at least in part through an early activation of the MMB-FOXM1 mitotic transcriptional program. We conclude that PKMYT1 inhibition is a promising therapeutic strategy for CCNE1-amplified cancers.
Asunto(s)
Ciclina E , Proteínas de la Membrana , Neoplasias Ováricas , Proteínas Serina-Treonina Quinasas , Proteínas Tirosina Quinasas , Proteína Quinasa CDC2 , Ciclina E/genética , Femenino , Amplificación de Genes , Regulación Neoplásica de la Expresión Génica , Humanos , Proteínas de la Membrana/genética , Neoplasias/genética , Neoplasias Ováricas/patología , Proteínas Serina-Treonina Quinasas/genética , Proteínas Tirosina Quinasas/genética , Mutaciones Letales SintéticasRESUMEN
This review brings to the forefront key synthetic modifications on natural products (NPs) that have yielded successful drugs. The emphasis is placed on the power of targeted chemical transformations in enhancing the therapeutic value of NPs through optimization of pharmacokinetics, stability, potency, and/or selectivity. Multiple classes of NPs such as macrolides, opioids, steroids, and ß-lactams used to treat a variety of conditions such as cancers, infections, inflammation are exemplified. Molecular modeling or X-ray structures of NP/protein complexes supporting the observed boost in therapeutic value of the modified NPs are also discussed. Significant advancement in synthetic chemistry, in structure determination, and in the understanding of factors controlling pharmacokinetics can now better position drug discovery teams to undertake NPs as valuable leads. We hope that the beneficial NPs synthetic modifications outlined here will reignite medicinal chemists' interest in NPs and their derivatives.
Asunto(s)
Productos Biológicos/química , Diseño de Fármacos , Analgésicos Opioides/química , Animales , Antibacterianos/química , Técnicas de Química Sintética , Cristalografía por Rayos X , Descubrimiento de Drogas , Humanos , Macrólidos/química , Modelos Moleculares , Estructura Molecular , Neoplasias/tratamiento farmacológico , Péptidos/química , Solubilidad , Solventes , Esteroides/química , Relación Estructura-Actividad , Taxoides/químicaAsunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Inhibidores Enzimáticos/farmacología , Kanamicina Quinasa/antagonistas & inhibidores , Paromomicina/análogos & derivados , Acetiltransferasas/antagonistas & inhibidores , Acinetobacter baumannii/efectos de los fármacos , Amicacina/metabolismo , Aminoglicósidos/química , Aminoglicósidos/farmacología , Cristalografía por Rayos X , Escherichia coli/efectos de los fármacos , Klebsiella pneumoniae/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Ribosomas/efectos de los fármacos , Ribosomas/metabolismo , Staphylococcus aureus/efectos de los fármacosRESUMEN
A series of 2"-O-substituted ether analogues of paromomycin were prepared based on new site-selective functionalizations. X-ray cocrystal complexes of several such analogues revealed a new mode of binding in the A-site rRNA, whereby rings I and II adopted the familiar orientation and position previously observed with paromomycin, but rings III and IV were oriented differently. With few exceptions, all of the new analogues showed potent inhibitory activity equal or better than paromomycin against a sensitive strain of S. aureus. Single digit microM MIC values were obtained against E. coli, with some of the ether appendages containing polar or basic end groups. Two analogues showed excellent survival rate in a mouse septicemia protection assay. Preliminary histopathological analysis of the kidney showed no overt signs of toxicity, while controls with neomycin and kanamycin were toxic at lower doses.