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Use of biomarkers in identifying cancer patients that will be responsive to treatment with a prmt5 inhibitor

A technology for inhibitors and patients, applied in the determination/testing of microorganisms, ICT adaptation, biomaterial analysis, etc.

Pending Publication Date: 2019-10-25
JANSSEN PHARMA NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

There are currently no such biomarkers

Method used

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  • Use of biomarkers in identifying cancer patients that will be responsive to treatment with a prmt5 inhibitor
  • Use of biomarkers in identifying cancer patients that will be responsive to treatment with a prmt5 inhibitor
  • Use of biomarkers in identifying cancer patients that will be responsive to treatment with a prmt5 inhibitor

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0108] Preparation of Intermediate 1

[0109]

[0110]To a mixture of 6-chloro-7-deazapurine β-d-nucleoside (25.0 g, 87.5 mmol) in acetone (330 mL) was added 2,2-dimethyl in one portion at 25 °C under N2 Oxypropane (18.2 g, 175 mmol) and 4-methylbenzenesulfonic acid (TosOH) (1.51 g, 8.75 mmol). The mixture was stirred at 60°C for 2 hours. The mixture was cooled to 25°C. The reaction was quenched by slow addition of saturated NaHCO3 (100 mL) and then extracted with ethyl acetate (125 mL x 5). The combined organic phases were washed with saturated brine (120 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (gradient elution: DCM / ethyl acetate from 1:0 to 2:1) to afford crude Intermediate 1 (38.0 g) as a pale yellow gum.

[0111] Preparation of intermediate 59

[0112]

[0113] Diisopropyl azodicarboxylate (0.221 mL, 1.125 mmol) was added dropwise to Intermediate 1 (0.27 g, 0.80 mmol), 3-bromo...

example 1

[0181] Example 1: PIK3CA activating mutations are associated with PRMT5 inhibitor sensitivity in SCLC.

[0182] The cellular sensitivity profile of Compound 2 was evaluated in the SCLC subclass of a broad panel of lung cancer cell lines. Strikingly, some of the most sensitive cell lines carried different gain-of-function mutations in the PIK3Cα gene and are mentioned in Table 2. Activation of the PI3Kα pathway (gain-of-function mutation or pathway stimulation) as a tumor response to standard therapy (cisplatin) or even to targeted drugs (like the latest generation of PARP inhibitors) implicates a key role in the resistance process, which May be associated with poor overall survival of SCLC patients after treatment.

[0183] cell line PIK3CA mutation Histological subtype GI50 NCI-H1048 H1047R SCLC 94.62nM LU99a T1025A SCLC 128.53nM H69V G106_R108del SCLC 85.62nM

[0184] Table 2

example 2

[0185] Example 2: In NSCLC, spliceosome alterations are associated with PRMT5 inhibitor sensitivity

[0186] Cancer-specific splicing events are known to initiate malignancy and also contribute to disease progression. So far, two proteins involved in splicing, U2AF1 and RBM10, have been described to be misregulated in NSCLC.

[0187] U2AF1 is a well-characterized splicing factor that carries a gain-of-function hotspot mutation (S34F) in 3%-8% of NSCLC patients. Recently, the RNA-binding protein RBM10, which is also critical for spliceosome assembly, has been classified as a tumor inactivated by loss-of-function mutations, mainly in NSCLC patients with a history of smoking (approximately 8%) inhibitory factor.

[0188] The Sm protein, which is critical for spliceosome assembly, has been described as a direct substrate of PRMT5, and thus, PRMT5 function is linked to regulating spliceosome activity.

[0189] Since the S34F gain-of-function mutation in U2AF1 has been identifi...

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Abstract

The present invention concerns a method of identifying a patient that is likely to be responsive to treatment with a protein arginine N-methyltransferase 5 (PRMT5) inhibitor comprising: evaluating a biological sample from the patient for the presence of a spliceosome alteration, wherein the presence of any said alteration indicates a higher likelihood for said patient to be responsive to treatmentwith said PRMT5 inhibitor than in the absence of any said mutation or alteration.

Description

technical field [0001] Provided herein are methods of identifying a patient with a high likelihood of responding to treatment with a protein arginine N-methyltransferase 5 inhibitor and methods of treating the patient. Background technique [0002] Protein arginine N-methyltransferase 5 (PRMT5), also described as Hsl7, Jbp1, Skb1, Capsuleen or Dart5, is the major enzyme responsible for mono- and symmetric-dimethylation of arginine One of the methyltransferases. PRMT5 belongs to the Sym Arg dimethyltransferase family. Catalytic activity is associated with activation of oncogenic lung driver pathways (splicing and WNT signaling) and epigenetic repression of tumor suppressors and tumor immunogenic chemokines. Protein levels and localization correlate with higher cellular methylation, loss of bronchial epithelial phenotype, and adverse disease progression. [0003] Post-translational arginine methylation on histones and non-histones is critical for diverse biological processe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12Q1/48C12Q1/6886G01N33/574
CPCC12Q1/48C12Q1/68C12Q1/6827C12Q2600/106C12Q2600/112C12Q2600/118G01N33/574G01N2800/52G16H50/30Y02A90/10A61K31/7064C12Q1/6886C12Q2600/158
Inventor D.布瑞梅L.贝克D.S.加弗尼C.H.莫伊
Owner JANSSEN PHARMA NV
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