The Broad Institute, Inc.

Dana-farber-cancer Institute Inc.

Bayer Pharma Aktiengesellschaft

Bayer Aktiengesellschaft

Xiaoyun Wu

Heidi Greulich

Philip Lienau

Matthew Meyerson

Timothy A Lewis

Martin Lange

Alex Burgin

Manuel Ellermann

Charlotte Christine Kopitz

Adrian Tersteegen

Detlev Sülzle

Stefan Nikolaus Gradl

Knut Eis

Antje Margret Wengner

Ulrike Sack

Luc De Waal

Monica Schenone

Christa Hegele-Hartung

Ulricke Sack

The present invention includes name compounds of general formula (I): (I) in which R, R, Rand Rare as defined herein, methods for their preparation, pharmaceutical compositions and combinations comprising said compounds, and their use for the treatment of hyperproliferative diseases.

1,2,4-triazin-3(2H)-one compounds for the treatment of hyperproliferative diseases

The present disclosure features methods for identifying pateints having a hyperproliferative disease, disorder, or condition responsive to phosphodiesterase 3 (PDE3) and schlafen family member 12 (SLFN12) complex formation. The hyperproliferative disease, disorder, or condition may be cancer in a patient including glioblastoma, melanoma, ovarian cancer, cervical cancer, sarcoma, or hematopoietic cancers, such as acute myeloid leukemia. Those responsive diseases, disorders, or conditions may be identified using the biomarker AIP and/or TRRAP in combination with those biomarkers pertinent to phosphodieseterase 3 and schlafen family member 12 complexes which may be formed by PDE3 modulation with certain active compounds. Expression of combinations of these biomarkers have been shown to correlate with active compound (e.g., PDE3 modulator, PDE3A modulator, PDE3B modulator) sensitivity.

Identification of PDE3 modulator responsive cancers

The present invention provides dihydrooxydiazinone compounds of general formula (I): in which R, R, R, and R, are as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of hyperproliferative diseases, as a sole agent or in combination with other active ingredients.

Dihydrooxadiazinones

The present invention features improved compounds, especially methods of identifying patients having cancer using biomarkers (e.g., PDE3A, SLFN12 and/or CREB3L1) that correlate with drug sensitivity and consequently treating a stratified patient population with an agent of the invention (e.g., Compounds 1-6 disclosed herein).

Compounds, compositions and methods for cancer patient stratification and cancer treatment

The present invention provides dihydrooxydiazinone compounds of general formula (I) in which R, R, R, and R, are as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of hyperproliferative diseases, as a sole agent or in combination with other active ingredients.

The present invention provides dihydrooxydiazinone compounds of general formula (I): in which R, R, R, and R, are as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of hyperproliferative diseases, as a sole agent or in combination with other active ingredients. 

The present invention features improved methods of identifying patients having cancer (e.g., melanoma, adenocarcinoma, lung, cervical, liver or breast cancer) using biomarkers (e.g., PDE3A, SLFN12) that correlate with drug sensitivity and consequently treating a stratified patient population with an agent of the invention (e.g., DNMDP, zardaverine, and anagrelide).

Compositions and methods for cancer expressing PDE3A or SLFN12

The present invention features improved compounds, especially the compound having the structure (1). Compositions and methods of identifying patients having cancer using biomarkers (e.g., PDE3A, PDE3B, SLFN12 and/or CREB3L1) that correlate with drug sensitivity and consequently treating a stratified patient population with an agent of the invention. 

Compounds, compositions and methods for cancer treatment

The present invention features improved Compounds, especially (I) methods of identifying patients having Cancer using biomarkers (e.g., PDE3A, SLFN12 and/or CREB3L1) that correlate with drug sensitivity and consequently treating a stratified patient population with an agent of the invention (e.g., Compounds 1-6 disclosed herein). 

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Cambridge, MA, United States of America

Xiaoyun Wu