RESUMEN
The status of industrial Medicinal Chemistry was discussed with European Medicinal Chemistry Leaders from large to mid-sized pharma and CRO companies as well as biotechs. The chemical modality space has expanded recently from small molecules to address new challenging targets. Besides the classical SAR/SPR optimization of drug molecules also their 'greenness' has increasing importance. The entire pharma discovery ecosystem has developed significantly. Beyond pharma and academia new key players such as Biotech and integrated CROs as well as Digital companies have appeared and are now to a large extend fueled by VC money. Digitalization is happening everywhere but surprisingly did not change speed and success rates of projects so far. Future Medicinal Chemists will still have to be excellent synthetic chemists but in addition they must be knowledgeable in new computational areas such as data sciences. Their ability to collaborate and to work in teams is key.
Asunto(s)
Química Farmacéutica , Industria Farmacéutica , Ecosistema , Europa (Continente)RESUMEN
Extension of the medicinal chemistry toolbox is in the vital interest of drug designers. However, the diffusion of an innovation can be a lengthy process. Along these lines, it took almost 70â years before the use of the sulfoximine group reached a critical mass in medicinal chemistry. Even though interest in this versatile functional group has increased exponentially in recent years, there is ample room for further innovative applications. This Review highlights emerging trends and opportunities for drug designers for the utilization of the sulfoximine group in medicinal chemistry, such as in the construction of complex molecules, proteolysis targeting chimeras (PROTACs), antibody-drug conjugates (ADCs) and novel warheads for covalent inhibition.
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Química Farmacéutica , Inmunoconjugados , ProteolisisRESUMEN
Eukaryotes have evolved two major pathways to repair potentially lethal DNA double-strand breaks. Homologous recombination represents a precise, DNA-template-based mechanism available during the S and G2 cell cycle phase, whereas non-homologous end joining, which requires DNA-dependent protein kinase (DNA-PK), allows for fast, cell cycle-independent but less accurate DNA repair. Here, we report the discovery of BAY-8400, a novel selective inhibitor of DNA-PK. Starting from a triazoloquinoxaline, which had been identified as a hit from a screen for ataxia telangiectasia and Rad3-related protein (ATR) inhibitors with inhibitory activity against ATR, ATM, and DNA-PK, lead optimization efforts focusing on potency and selectivity led to the discovery of BAY-8400. In in vitro studies, BAY-8400 showed synergistic activity of DNA-PK inhibition with DNA damage-inducing targeted alpha therapy. Combination of PSMA-targeted thorium-227 conjugate BAY 2315497 treatment of human prostate tumor-bearing mice with BAY-8400 oral treatment increased antitumor efficacy, as compared to PSMA-targeted thorium-227 conjugate monotherapy.
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Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Proteína Quinasa Activada por ADN/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Animales , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular , Proteína Quinasa Activada por ADN/genética , Sinergismo Farmacológico , Quimioterapia Combinada , Hepatocitos/efectos de los fármacos , Humanos , Ratones , Estructura Molecular , Fosfatidilinositol 3-Quinasas/genética , Ratas , Relación Estructura-Actividad , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Selective inhibition of exclusively transcription-regulating positive transcription elongation factor b/CDK9 is a promising new approach in cancer therapy. Starting from atuveciclib, the first selective CDK9 inhibitor to enter clinical development, lead optimization efforts aimed at identifying intravenously (iv) applicable CDK9 inhibitors with an improved therapeutic index led to the discovery of the highly potent and selective clinical candidate VIP152. The evaluation of various scaffold hops was instrumental in the identification of VIP152, which is characterized by the underexplored benzyl sulfoximine group. VIP152 exhibited the best preclinical overall profile in vitro and in vivo, including high efficacy and good tolerability in xenograft models in mice and rats upon once weekly iv administration. VIP152 has entered clinical trials for the treatment of cancer with promising longterm, durable monotherapy activity in double-hit diffuse large B-cell lymphoma patients.
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Antineoplásicos/farmacología , Quinasa 9 Dependiente de la Ciclina/antagonistas & inhibidores , Descubrimiento de Drogas , Leucemia Mieloide Aguda/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Quinasa 9 Dependiente de la Ciclina/metabolismo , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Inyecciones Intravenosas , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Ratones , Ratones Desnudos , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/química , Ratas , Relación Estructura-ActividadRESUMEN
We describe the assembly and annotation of a chemogenomic set of protein kinase inhibitors as an open science resource for studying kinase biology. The set only includes inhibitors that show potent kinase inhibition and a narrow spectrum of activity when screened across a large panel of kinase biochemical assays. Currently, the set contains 187 inhibitors that cover 215 human kinases. The kinase chemogenomic set (KCGS), current Version 1.0, is the most highly annotated set of selective kinase inhibitors available to researchers for use in cell-based screens.
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Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/química , Bibliotecas de Moléculas Pequeñas/química , Humanos , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Relación Estructura-ActividadRESUMEN
The ATR kinase plays a key role in the DNA damage response by activating essential signaling pathways of DNA damage repair, especially in response to replication stress. Because DNA damage and replication stress are major sources of genomic instability, selective ATR inhibition has been recognized as a promising new approach in cancer therapy. We now report the identification and preclinical evaluation of the novel, clinical ATR inhibitor BAY 1895344. Starting from quinoline 2 with weak ATR inhibitory activity, lead optimization efforts focusing on potency, selectivity, and oral bioavailability led to the discovery of the potent, highly selective, orally available ATR inhibitor BAY 1895344, which exhibited strong monotherapy efficacy in cancer xenograft models that carry certain DNA damage repair deficiencies. Moreover, combination treatment of BAY 1895344 with certain DNA damage inducing chemotherapy resulted in synergistic antitumor activity. BAY 1895344 is currently under clinical investigation in patients with advanced solid tumors and lymphomas (NCT03188965).
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Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Proteínas de la Ataxia Telangiectasia Mutada/antagonistas & inhibidores , Morfolinas/administración & dosificación , Morfolinas/farmacocinética , Pirazoles/administración & dosificación , Pirazoles/farmacocinética , Administración Oral , Animales , Antineoplásicos/química , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Proteínas de la Ataxia Telangiectasia Mutada/química , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Disponibilidad Biológica , Carboplatino/administración & dosificación , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Inhibidores del Citocromo P-450 CYP2C8/química , Inhibidores del Citocromo P-450 CYP2C8/farmacología , Reparación del ADN/efectos de los fármacos , Perros , Descubrimiento de Drogas , Ensayos de Selección de Medicamentos Antitumorales , Estabilidad de Medicamentos , Femenino , Humanos , Ratones SCID , Microsomas Hepáticos/efectos de los fármacos , Morfolinas/química , Pirazoles/química , Ratas Wistar , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Sulfonimidamides present exciting opportunities as chiral isosteres of sulfonamides, with potential for additional directional interactions. Here, we present the first modular enantioselective synthesis of sulfonimidamides, including the first stereoselective synthesis of enantioenriched sulfonimidoyl fluorides, and studies on their reactivity. A new route to sulfonimidoyl fluorides is presented from solid bench-stable, N-Boc-sulfinamide (Boc=tert-butyloxycarbonyl) salt building blocks. Enantioenriched arylsulfonimidoyl fluorides are shown to be readily racemised by fluoride ions. Conditions are developed, which trap fluoride and enable the stereospecific reaction of sulfonimidoyl fluorides with primary and secondary amines (100 %â es, es=enantiospecificity) generating sulfonimidamides with up to 99 %â ee. Aryl and alkyl sulfonimidoyl fluoride reagents are suitable for mild late stage functionalisation reactions, exemplified by coupling with a selection of complex amines in marketed drugs.
RESUMEN
A short synthetic approach with broad scope to access five- to seven-membered cyclic sulfoximines in only two to three steps from readily available thiophenols is reported. Thus, simple building blocks were converted to complex molecular structures by a sequence of S-alkylation and one-pot sulfoximine formation, followed by intramolecular cyclization. Seventeen structurally diverse cyclic sulfoximines were prepared in high overall yields. In vitro evaluation of these underrepresented, three-dimensional, cyclic sulfoximines with respect to properties relevant to medicinal chemistry did not reveal any intrinsic flaw for application in drug discovery.
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Descubrimiento de Drogas/métodos , Metionina Sulfoximina/síntesis química , Alquilación , Química Farmacéutica , Ciclización , Metionina Sulfoximina/química , Estructura MolecularRESUMEN
The DNA damage response (DDR) secures the integrity of the genome of eukaryotic cells. DDR deficiencies can promote tumorigenesis but concurrently may increase dependence on alternative repair pathways. The ataxia telangiectasia and Rad3-related (ATR) kinase plays a central role in the DDR by activating essential signaling pathways of DNA damage repair. Here, we studied the effect of the novel selective ATR kinase inhibitor BAY 1895344 on tumor cell growth and viability. Potent antiproliferative activity was demonstrated in a broad spectrum of human tumor cell lines. BAY 1895344 exhibited strong monotherapy efficacy in cancer xenograft models that carry DNA damage repair deficiencies. The combination of BAY 1895344 with DNA damage-inducing chemotherapy or external beam radiotherapy (EBRT) showed synergistic antitumor activity. Combination treatment with BAY 1895344 and DDR inhibitors achieved strong synergistic antiproliferative activity in vitro, and combined inhibition of ATR and PARP signaling using olaparib demonstrated synergistic antitumor activity in vivo Furthermore, the combination of BAY 1895344 with the novel, nonsteroidal androgen receptor antagonist darolutamide resulted in significantly improved antitumor efficacy compared with respective single-agent treatments in hormone-dependent prostate cancer, and addition of EBRT resulted in even further enhanced antitumor efficacy. Thus, the ATR inhibitor BAY 1895344 may provide new therapeutic options for the treatment of cancers with certain DDR deficiencies in monotherapy and in combination with DNA damage-inducing or DNA repair-compromising cancer therapies by improving their efficacy.
Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada/antagonistas & inhibidores , Daño del ADN/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Animales , Femenino , Humanos , RatonesRESUMEN
The human luteinizing hormone receptor (hLH-R) is a member of the glycoprotein hormone family of G-protein-coupled receptors (GPCRs), activated by luteinizing hormone (hLH) and essentially involved in the regulation of sex hormone production. Thus, hLH-R represents a valid target for the treatment of sex hormone-dependent cancers and diseases (polycystic ovary syndrome, uterine fibroids, endometriosis) as well as contraception. Screening of the Bayer compound library led to the discovery of tetrahydrothienopyridine derivatives as novel, small-molecule (SMOL) hLH-R inhibitors and to the development of BAY-298, the first nanomolar hLH-R antagonist reducing sex hormone levels in vivo. Further optimization of physicochemical, pharmacokinetic, and safety parameters led to the identification of BAY-899 with an improved in vitro profile and proven efficacy in vivo. BAY-298 and BAY-899 serve as valuable tool compounds to study hLH-R signaling in vitro and to interfere with the production of sex hormones in vivo.
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Estradiol/sangre , Naftiridinas/química , Receptores de HL/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Relación Dosis-Respuesta a Droga , Canal de Potasio ERG1/metabolismo , Femenino , Células de la Granulosa/efectos de los fármacos , Ensayos Analíticos de Alto Rendimiento , Humanos , Masculino , Ratones , Microsomas Hepáticos/efectos de los fármacos , Ovulación/efectos de los fármacos , Ovulación/genética , Progesterona/sangre , Ratas Wistar , Receptores de HFE/antagonistas & inhibidores , Receptores de HL/metabolismo , Relación Estructura-Actividad , Testosterona/sangreRESUMEN
Onset of progression even during therapy with novel drugs remains an issue in chronic lymphocytic leukemia (CLL). Thus, there is ongoing demand for novel agents. Approaches targeting cyclin-dependent kinases (CDK) have reached the clinical trial stage. CDK9 mediating RNA transcriptional elongation is the evolving pivotal CLL CDK inhibitor target. However, more CDK9 selective compounds are desirable. Here, we describe the CDK9 inhibitor LDC526 displaying a low nanomolar biochemical activity against CDK9 and an at least 50-fold selectivity against other CDKs. After demonstrating in vitro MEC-1 cell line and primary human CLL cell cytotoxicity we evaluated the LDC526 in vivo effect on human CLL cells transplanted into NOD/scid/γcnull (NSG) mice. LDC526 administration (75 mg/kg) for 5 days resulted in a 77% reduction of human CLL cells in NSG spleens compared to carrier control treatment. Next, we longitudinally studied the LDC526 impact on circulating CLL cells in the TCL1 transgenic mouse model. LDC526 (50 mg/kg) administration for two days led to a 16-fold reduction of blood CLL cell numbers. Remarkably, residual CLL cells exhibited significantly increased intracellular BCL-2 levels. However, the LDC526 cytotoxic effect was not restricted to CLL cells as also declining numbers of normal B and T lymphocytes were observed in LDC526 treated TCL1 mice. Taken together, our in vivo data provide a strong rational for continued LDC526 development in CLL therapy and argue for the combination with BCL-2 inhibitors.
RESUMEN
An unprecedented set of structurally diverse sulfonimidamides (47â compounds) has been prepared by various N-functionalization reactions of tertiary =NH sulfonimidamide 2 aa. These N-functionalization reactions of model compoundâ 2 aa include arylation, alkylation, trifluoromethylation, cyanation, sulfonylation, alkoxycarbonylation (carbamate formation) and aminocarbonylation (urea formation). Small molecule X-ray analyses of selected N-functionalized products are reported. To gain further insight into the properties of sulfonimidamides relevant to medicinal chemistry, a variety of structurally diverse reaction products were tested in selected in vitro assays. The described N-functionalization reactions provide a short and efficient approach to structurally diverse sulfonimidamides which have been the subject of recent, growing interest in the life sciences.
RESUMEN
Selective inhibition of exclusively transcription-regulating PTEFb/CDK9 is a promising new approach in cancer therapy. Starting from lead compound BAY-958, lead optimization efforts strictly focusing on kinase selectivity, physicochemical and DMPK properties finally led to the identification of the orally available clinical candidate atuveciclib (BAYâ 1143572). Structurally characterized by an unusual benzyl sulfoximine group, BAYâ 1143572 exhibited the best overall profile inâ vitro and inâ vivo, including high efficacy and good tolerability in xenograft models in mice and rats. BAYâ 1143572 is the first potent and highly selective PTEFb/CDK9 inhibitor to enter clinical trials for the treatment of cancer.
Asunto(s)
Quinasa 9 Dependiente de la Ciclina/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Sulfonamidas/uso terapéutico , Triazinas/uso terapéutico , Animales , Sitios de Unión , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cristalografía por Rayos X , Quinasa 9 Dependiente de la Ciclina/metabolismo , Semivida , Células HeLa , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Ratones , Ratones Desnudos , Conformación Molecular , Simulación del Acoplamiento Molecular , Neoplasias/patología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/toxicidad , Estructura Terciaria de Proteína , Ratas , Ratas Desnudas , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/toxicidad , Trasplante Heterólogo , Triazinas/química , Triazinas/toxicidadRESUMEN
Unprotected tertiary sulfonimidamides have been prepared in good to excellent yields in a one-pot transformation from tertiary sulfinamides through NH transfer. The reaction is mediated by commercially available (diacetoxyiodo)benzene and ammonium carbamate in methanol under convenient conditions. A wide range of functional groups are tolerated and initial results indicate that the NH transfer is stereospecific. A small molecule X-ray analysis of NH sulfonimidamide 2 a and its behavior in selected inâ vitro assays in comparison to the matched sulfonamide are also reported. This new reaction provides a safe, short and efficient approach to sulfonimidamides, which have been the subject of recent, growing interest in the life sciences.
RESUMEN
Sulfoximines have gained considerable recognition as an important structural motif in drug discovery of late. In particular, the clinical kinase inhibitors for the treatment of cancer, roniciclib (pan-CDK inhibitor), BAYâ 1143572 (P-TEFb inhibitor), and AZDâ 6738 (ATR inhibitor), have recently drawn considerable attention. Whilst the interest in this underrepresented functional group in drug discovery is clearly on the rise, there remains an incomplete understanding of the medicinal-chemistry-relevant properties of sulfoximines. Herein we report the synthesis and inâ vitro characterization of a variety of sulfoximine analogues of marketed drugs and advanced clinical candidates to gain a better understanding of this neglected functional group and its potential in drug discovery.
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Diseño de Fármacos , Inhibidores de Proteínas Quinasas/química , Sulfóxidos/química , Aminopiridinas/síntesis química , Aminopiridinas/química , Aminopiridinas/metabolismo , Proteínas de la Ataxia Telangiectasia Mutada/antagonistas & inhibidores , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Quinasas Ciclina-Dependientes/metabolismo , Estradiol/análogos & derivados , Estradiol/síntesis química , Estradiol/química , Estradiol/metabolismo , Fulvestrant , Mesilato de Imatinib/síntesis química , Mesilato de Imatinib/química , Mesilato de Imatinib/metabolismo , Piperazinas/síntesis química , Piperazinas/química , Piperazinas/metabolismo , Piperidinas/síntesis química , Piperidinas/química , Piperidinas/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/metabolismo , Purinas/síntesis química , Purinas/química , Purinas/metabolismo , Pirazoles/síntesis química , Pirazoles/química , Pirazoles/metabolismo , Piridinas/síntesis química , Piridinas/química , Piridinas/metabolismo , Sulfóxidos/síntesis química , Sulfóxidos/metabolismo , Diclorhidrato de Vardenafil/síntesis química , Diclorhidrato de Vardenafil/química , Diclorhidrato de Vardenafil/metabolismoRESUMEN
Roniciclib (BAY 1000394) is a type I pan-CDK (cyclin-dependent kinase) inhibitor which has revealed potent efficacy in xenograft cancer models. Here, we show that roniciclib displays prolonged residence times on CDK2 and CDK9, whereas residence times on other CDKs are transient, thus giving rise to a kinetic selectivity of roniciclib. Surprisingly, variation of the substituent at the 5-position of the pyrimidine scaffold results in changes of up to 3 orders of magnitude of the drug-target residence time. CDK2 X-ray cocrystal structures have revealed a DFG-loop adaption for the 5-(trifluoromethyl) substituent, while for hydrogen and bromo substituents the DFG loop remains in its characteristic type I inhibitor position. In tumor cells, the prolonged residence times of roniciclib on CDK2 and CDK9 are reflected in a sustained inhibitory effect on retinoblastoma protein (RB) phosphorylation, indicating that the target residence time on CDK2 may contribute to sustained target engagement and antitumor efficacy.
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Antineoplásicos/farmacocinética , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 9 Dependiente de la Ciclina/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacocinética , Pirimidinas/farmacocinética , Sulfóxidos/farmacocinética , Animales , Antineoplásicos/sangre , Antineoplásicos/química , Aurora Quinasa A/antagonistas & inhibidores , Células HeLa , Humanos , Cinética , Células MCF-7 , Ratones , Inhibidores de Proteínas Quinasas/sangre , Inhibidores de Proteínas Quinasas/química , Pirimidinas/sangre , Pirimidinas/química , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Sulfonamidas/farmacocinética , Sulfóxidos/sangre , Sulfóxidos/químicaRESUMEN
Androgen receptor (AR) mutations arise in patients developing resistance to hormone deprivation therapies. Here we describe BAY 1024767, a thiohydantoin derivative with strong antagonistic activity against nine AR variants with mutations located in the AR ligand-binding domain (LBD), and against wild-type AR. Antagonism was maintained, though reduced, at increased androgen levels. Anti-tumor efficacy was evidenced in vivo in the KuCaP-1 prostate cancer model which bears the W741C bicalutamide resistance mutation and in the syngeneic prostate cancer rat model Dunning R3327-G. The prevalence of six selected AR mutations was determined in plasma DNA originating from 100 resistant patients and found to be at least 12%. Altogether the results show BAY 1024767 to be a strong antagonist for several AR mutants linked to therapy resistance, which opens the door for next-generation compounds that can benefit patients based on their mutation profile.
Asunto(s)
Antagonistas de Receptores Androgénicos/farmacología , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Receptores Androgénicos/genética , Tiohidantoínas/farmacología , Animales , Células COS , Células CACO-2 , Línea Celular Tumoral , Chlorocebus aethiops , Regulación hacia Abajo , Humanos , Masculino , Ratones , Ratones SCID , Mutación , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Distribución Aleatoria , Ratas , Receptores Androgénicos/metabolismo , Transfección , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Innovation has frequently been described as the key to drug discovery. However, in the daily routine, medicinal chemists often tend to stick to the functional groups and structural elements they know and love. Blockbuster cancer drug Velcade (bortezomib), for example, was rejected by more than 50 companies, supposedly because of its unusual boronic acid function (as often repeated: "only a moron would put boron in a drug!"). Similarly, in the discovery process of the pan-CDK inhibitor BAY 1000394, the unconventional proposal to introduce a sulfoximine group into the lead series also led to sneers and raised eyebrows, since sulfoximines have seldom been used in medicinal chemistry. However, it was the introduction of the sulfoximine group that finally allowed the fundamental issues of the project to be overcome, culminating in the identification of the clinical sulfoximine pan-CDK inhibitor BAY 1000394. This Minireview provides an overview of a widely neglected opportunity in medicinal chemistry--the sulfoximine group.
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Química Farmacéutica/tendencias , Metionina Sulfoximina/química , Proteínas Inhibidoras de las Quinasas Dependientes de la Ciclina/química , Humanos , Estructura Molecular , Pirimidinas/química , Sulfóxidos/químicaRESUMEN
Lead optimization of a high-throughput screening hit led to the rapid identification of aminopyrimidine ZKâ 304709, a multitargeted CDK and VEGF-R inhibitor that displayed a promising preclinical profile. Nevertheless, ZKâ 304709 failed in phaseâ I studies due to dose-limited absorption and high inter-patient variability, which was attributed to limited aqueous solubility and off-target activity against carbonic anhydrases. Further lead optimization efforts to address the off-target activity profile finally resulted in the introduction of a sulfoximine group, which is still a rather unusual approach in medicinal chemistry. However, the sulfoximine series of compounds quickly revealed very interesting properties, culminating in the identification of the nanomolar pan-CDK inhibitor BAYâ 1000394, which is currently being investigated in phaseâ I clinical trials.
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Antineoplásicos/farmacología , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Descubrimiento de Drogas , Neoplasias Experimentales/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Sulfóxidos/farmacología , Neoplasias del Cuello Uterino/tratamiento farmacológico , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/síntesis química , Quinasas Ciclina-Dependientes/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Células HeLa , Ensayos Analíticos de Alto Rendimiento , Humanos , Ratones , Modelos Moleculares , Estructura Molecular , Peso Molecular , Neoplasias Experimentales/enzimología , Neoplasias Experimentales/metabolismo , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/síntesis química , Pirimidinas/administración & dosificación , Pirimidinas/síntesis química , Ratas , Relación Estructura-Actividad , Sulfóxidos/administración & dosificación , Sulfóxidos/síntesis química , Neoplasias del Cuello Uterino/enzimología , Neoplasias del Cuello Uterino/metabolismoRESUMEN
Deregulated activity of cyclin-dependent kinases (CDK) results in loss of cell-cycle checkpoint function and increased expression of antiapoptotic proteins, which has been directly linked to the molecular pathology of cancer. BAY 1000394 inhibits the activity of cell-cycle CDKs CDK1, CDK2, CDK3, CDK4, and of transcriptional CDKs CDK7 and CDK9 with IC(50) values in the range between 5 and 25 nmol/L. Cell proliferation was inhibited at low nanomolar concentration in a broad spectrum of human cancer cell lines. In cell-based assays, the inhibition of phosphorylation of the CDK substrates retinoblastoma protein, nucleophosmin, and RNA polymerase II was shown. Cell-cycle profiles were consistent with inhibition of CDK 1, 2, and 4 as shown in cell-cycle block and release experiments. The physicochemical and pharmacokinetic properties of BAY 1000394 facilitate rapid absorption and moderate oral bioavailability. The compound potently inhibits growth of various human tumor xenografts on athymic mice including models of chemotherapy resistance upon oral dosing. Furthermore, BAY 1000394 shows more than additive efficacy when combined with cisplatin and etoposide. These results suggest that BAY 1000394 is a potent pan-CDK inhibitor and a novel oral cytotoxic agent currently in phase I clinical trials.