Dual Mechanism Kinase Inhibitors

Experience with our PIM kinase program suggested that PIM kinase inhibition could usefully combine with inhibition of a number of other signalling pathways to produce a profound reduction in cancer cell growth.

Some of the most marked synergies were observed when PIM kinase inhibition was combined with inhibitors of PI3 kinase. Subsequent research has shown that PIM acts as the primary escape pathway for PI3K/AKT/mTOR signalling. When this pathway is blocked there is a marked elevation in PIM expression in a number of cancer cell types.

A combined inhibitor of PIM and PI3K would have a dual advantage in being more efficacious in arresting tumour cell growth and also prevent the emergence of the resistance that has been observed with PI3K inhibitors in the clinic. Combining these activities into a single molecule has enormous advantages across the cycle from development costs to patient convenience.

Inflection is developing a series of molecules which selectively inhibit PIM and PI3K without affecting the activity of other kinases. The pipeline includes IBL-202 (a PIM/PI3k inhibitor) and the IBL-300 series (PIM/PI3k/mTOR inhibitors). These molecules are significantly more active than compounds that act on either mechanism alone. Pre-clinical data to date suggests utility in both haematological malignancies and solid tumours.

Further in vitro and in vivo testing is underway to optimally characterise the efficacy profile of this dual mechanism kinase inhibitor program.

Poster Presentations:

“The dual PIM/PI3-kinase inhibitor IBL-202 is effective against CLL cells cultured under conditions that mimic the hypoxic tumour microenvironment”

International Workshop on Chronic Lymphocytic Leukaemia  (iwCLL) 2017, New York City, May 15-17. Link to abstract here.

"Elucidating the Role of PIM Kinase and Its Therapeutic Potential in NSCLC" and "Resistance Mechanisms to PI3K-mTOR Inhibition in NSCLC"

17th IASLC World Conference on Lung Cancer, Vienna, December 4-7, 2016. Link to abstracts here.

"Targeting PIM kinase in NSCLC"

International Association of Lung Cancer (IASLC) 16th World Conference on Lung Cancer in Denver, CO September 6-9, 2015. Link to abstract here.

“Dual inhibition of PIM and PI3-kinase by IBL-202 is effective against CLL cells cultured under conditions that mimic the hypoxic tumour microenvironment” 

International Workshop on Chronic Lymphocytic Leukaemia 2015, September 7-9, 2015 in Sydney, Australia. Link to interview with Dr. Giles Best here.

"Initial Evaluation of Novel Dual PIM/PI3K and Triple PIM/PI3K/MTOR inhibitors in multiple myeloma"

20th Congress of the European Hematology Association (EHA) June 11 – 14, 2015, Vienna. Link to abstract here.

 “Dual Inhibition of PIM and PI3-Kinase by IBL-202 is Highly Synergistic Compared to Mono-Molecular Inhibition and Represents a Novel Treatment Strategy for Chronic Lymphocytic Leukemia

56th Annual Meeting of the American Society for Haematology (ASH), December 6-9, 2014 San Francisco, California. Link to abstract here

 “Combined inhibition of PIM and PI3 kinases shows an enhanced efficacy in a number of solid tumour cell lines

American Association for Cancer Research (AACR) Annual Meeting 2014, April 5-9, San Diego, California. Link to abstract here

 “Co-targeting PIM and PI3K/mTOR pathways with a single molecule: Novel orally available combined PIM/PI3K and PIM/PI3K/mTOR kinases inhibitors

2013 AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics Conference, Boston, USA. 

 

To request a copy of the corresponding poster please email the company at bd@inflectionbio.com

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