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Structure Guided Optimization, in Vitro Activity, and in Vivo Activity of Pan-PIM Kinase Inhibitors
Matthew T Burger1, Wooseok Han1, Jiong Lan1
1Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
Abstract:
Proviral insertion of Moloney virus (PIM) 1, 2, and 3 kinases are serine/threonine kinases that normally function in survival and proliferation of hematopoietic cells. As high expression of PIM1, 2, and 3 is frequently observed in many human malignancies, including multiple myeloma, non-Hodgkins lymphoma, and myeloid leukemias, there is interest in determining whether selective PIM inhibition can improve outcomes of these human cancers. Herein, we describe our efforts toward this goal. The structure guided optimization of a singleton high throughput screening hit in which the potency against all three PIM isoforms was increased >10,000-fold to yield compounds with pan PIM K is < 10 pM, nanomolar cellular potency, and in vivo activity in an acute myeloid leukemia Pim-dependent tumor model is described.
Insights
Researchers developed potent inhibitors targeting PIM kinases (proviral insertion Moloney virus), crucial for cancer cell survival. These novel compounds show promise for treating hematologic malignancies like leukemia.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- PIM kinases (proviral insertion Moloney virus 1, 2, and 3) are serine/threonine kinases vital for hematopoietic cell survival and proliferation.
- Elevated PIM kinase expression is common in various human cancers, including multiple myeloma, non-Hodgkin's lymphoma, and myeloid leukemias.
Purpose of the Study:
- To investigate the therapeutic potential of selective PIM kinase inhibition in human cancers.
- To develop novel small molecules targeting PIM kinases for cancer treatment.
Main Methods:
- Structure-guided optimization of a high-throughput screening hit.
- Assays to determine kinase inhibition (K) and cellular potency.
- In vivo studies using an acute myeloid leukemia tumor model dependent on PIM kinase activity.
Main Results:
- Achieved a >10,000-fold increase in potency against all three PIM isoforms.
- Developed compounds with picomolar (pM) pan-PIM kinase inhibition.
- Demonstrated nanomolar cellular potency and significant in vivo efficacy in a relevant preclinical cancer model.
Conclusions:
- Selective PIM kinase inhibition represents a promising therapeutic strategy for hematologic malignancies.
- The developed compounds exhibit potent and selective PIM inhibition with demonstrated in vivo anti-cancer activity.
