H. Lee Moffitt Cancer Center and Research Institute, Inc.

Kiran N Mahajan

Nupam Mahajan

Nicholas James Lawrence

Harshani Lawrence

Nupam P Mahajan

Described are cancer therapies and anti-cancer compounds. In particular, disclosed are inhibitors of ACK1 tyrosine kinase and their use in the treatment of cancer. Methods of screening for new ACK1 tyrosine kinase inhibitors are also disclosed. In specific example, compound having Formula I are disclosed.

Inhibitors of ACK1/TNK2 tyrosine kinase

Described are cancer therapies and anti-cancer compounds. In particular, disclosed are inhibitors of Ack1 tyrosine kinase and their use in the treatment of cancer. Methods of screening for new Ack1 tyrosine kinase inhibitors are also disclosed. In specific example, compound having Formula I through IV are disclosed.

Phosphorylation of histones was observed at certain tyrosine residues which have not been associated with epigenetic modification. These sites include H2B Tyr37, H4 Tyr88 and Tyr 51 and H3 Tyr99. Kinases responsible for the phosphorylation as well as downstream genes regulated by such phosphorylation were also identified. Antibodies that are specific to such phosphorylated histones have been generated, which are useful for detecting the phosphorylation and related events. With such findings, the present disclosure provides compositions and methods for disease diagnosis, prognosis and therapy selection, in particular for cancer, obesity and diabetes.

Phosphorylation of histones and uses thereof

AKT/PKB kinase is a key signaling component of one of the most frequently activated pathways in cancer and is a major target of cancer drug development. The present study uncovered that growth factors binding to RTKs lead to activation of a non-receptor tyrosine kinase, Ack1 (TNK2), which directly phosphorylates AKT at a conserved tyrosine 176 residue. Tyr176-phosphorylated AKT binds to phosphatidic acid and localizes to the plasma membrane, leading to AKT activation. Expression levels of Tyr176-phosphorylated-AKT and Tyr284-phosphorylated-Ack1 were positively correlated with the severity of disease progression, and inversely correlated with the survival of breast, prostate, lung and pancreatic cancer patients.

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Tampa, FL, United States of America

Kiran N Mahajan