Dana-farber-cancer Institute Inc.

Novartis Ag

Yubao Wang

Jean Zhao

Nathanael Schiander Gray

Hwan Geun Choi

Tinghu Zhang

Hai-Tsang Huang

Xizhong Huang

Junxia Min

Jean J Zhao

Provided herein are small molecule inhibitors of maternal embryonic leucine zipper kinase (MELK) having the structure of formula (I), wherein X and R-Rare defined in the specification. The compounds are useful for treating cancer and other conditions or diseases associated with aberrant MELK expression. Also provided herein are pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier. The invention also provides methods of treating cancers associated with over-expression of MELK.

Salicylate inhibitors of MELK and methods of use

Provided herein are tricyclic small molecule inhibitors of maternal embryonic leucine zipper kinase (MELK). The compounds are useful for treating cancer and other conditions or diseases associated with aberrant MELK expression. Also provided herein are pharmaceutical compositions comprising a tricyclic compound of the invention and a pharmaceutically acceptable carrier. The invention also provides methods of treating cancers associated with over-expression of MELK.

Tricyclic kinase inhibitors of MELK and methods of use

The methods of the present invention, relate to the surprising determination that the level of phosphorylation of position 406 (e.g., a serine residue) of human eukaryotic initiation factor 4B (eIF4B), or a corresponding phosphorylatable amino acid of an ortholog thereof, serves as a biomarker for MELK enzymatic (e.g., kinase) and/or oncogenic activity. The methods of the present invention further relate to the surprising determination that the level of phosphorylation of position 3 (e.g., a threonine residue) and/or position 10 (e.g., a serine residue) and/or position 11 (e.g., a threonine residue) of human Histone M3, or a corresponding phosphorylatable amino acid of an ortholog thereof, also serves as a biomarker for MELK enzymatic (e.g., kinase) and/or oncogenic activity.

Biomarker for MELK activity and methods of using same

Methods for inhibiting growth or proliferation of breast cancer cells are provided. The methods include administering to a subject in need thereof in an amount that is effective to inhibit growth or proliferation of the breast cancer cells a MELK inhibitor, wherein the breast cancer cells are estrogen receptor (ER) negative. In some aspects, the methods include administering to a subject in need thereof in an amount that is effective to inhibit growth or proliferation of the breast cancer cells a MELK inhibitor, a FoxM1 inhibitor or a MELK inhibitor and a FoxM1 inhibitor, wherein the breast cancer cells are estrogen receptor (ER) negative. Methods of treatment for breast cancer and methods of identifying patients having cancer that are likely to benefit from treatment with a MELK inhibitor, a FoxM1 inhibitor or a MELK inhibitor and a FoxM1 inhibitor are also provided.

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Newton, MA, United States of America

Yubao Wang