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University of Wisconsin-Madison

Pharm Sci Seminar – Herman Sintim

January

26,

2018

Herman O. Sintim, PhD
Department of Chemistry and Center for Drug Discovery
Purdue University
Host: Weiping Tang

Towards a complete cure for leukemia- inhibiting cancer driver kinases and collaborating kinases with novel polypharmacophores

Chronic myeloid leukemia, CML, is driven by ABL1 and the introduction of highly effective kinase inhibitors, such as imatinib, has resulted in a 5-year survival rate for CML to approach 90%. On the contrary, the 5-year survival rate for acute myeloid leukemia, AML, is ~30%. For patients over 60 years, the 5-year survival is abysmal (3-8%). Clearly breakthroughs in AML therapeutics are needed. About 30% of AML patients are FLT3-ITD-positive and midostaurin, a multikinase inhibitor with activity against FLT3 was recently approved by the FDA. Most FLT3 inhibitors produce an initial clinical response but FLT3-ITD-positive patients ultimately relapse due to secondary mutations in the TKD, especially D835 or F691 mutations. Using “one-flask” reactions we generated a new class of type I and II polypharmacophore kinase inhibitors that inhibit FLT3 kinase and all clinically relevant FLT3 secondary mutations. In addition to being potent against drug-resistant FLT3 kinase, our lead molecules also inhibit downstream kinases that collaborate with FLT3 to exacerbate AML, such as Src-family, MNK2 and TOPK kinases. Despite being polypharmacophores, these molecules are selective and did not inhibit over 400 other kinases. In vivo, these new anti-AML compounds completely cleared leukemia from mice. Our new generation compounds have a high potential for clinical translation.

 

Date
Friday, January 26, 2018
Time
4:00 PM – 5:00 PM

This event is brought to you by: Pharmaceutical Sciences Division