Dual Mechanism Kinase Inhibitors

Inflection Biosciences’ dual mechanism cancer drug program is the first of its kind rationally designed to target two well-known cancer pathways, PIM kinase and PI3K. Our first-in-class drug pipeline has potential utility in solid tumours such as breast cancer and in a range of blood cancers including acute myeloid leukaemia.

A powerful combination

PIM kinase (proto-oncogene proviral integration site for moloney murine leukemia virus) is known to be involved in critical cell signalling pathways that regulate processes including cell cycle progression, apoptosis and transcriptional activation. In recognition of the growing understanding of the role of PIM kinase in cancer there are now PIM kinase inhibitors in early stages of clinical development. 

Recent developments in cancer biology show that multiple targets likely need to be simultaneously targeted in cancer cells to prevent resistance and maximize activity. Experience with our own PIM kinase program indicated that it could usefully combine with inhibition of other signalling pathways to produce a significant reduction in cancer cell growth. Some of the most marked synergies were observed when PIM kinase inhibition was combined with inhibitors of PI3 kinase. The PI3K (phosphoinositide 3-kinase) signalling pathway plays a critical role in the regulation of cancer cell growth, survival and proliferation. Given the prevalence of the PI3K pathway in cancer it has been of considerable interest to the industry. Two PI3-kinase inhibitor drugs have already been approved (Zydelig® and AliqopaTM) in leukemia/lymphoma however PI3K inhibitors have yet to make their mark in solid tumours such as breast or lung cancer. 

Researchers at the Dana-Farber Cancer Institute offered an explanation for this limited effect of PI3K inhibitors. They have shown that while PI3K kinase inhibition is effective in arresting the growth of cancer cells, used alone it may allow surviving quiescent cancer cells to develop resistance, leaving a reservoir of cells that can regrow and cause the cancer to return (W. Hahn; eLIFE; May 2017).  This group demonstrated that co-targeting PIM kinase inhibition alongside PI3K inhibition converts the cell cycle arrest induced by PI3K inhibition into apoptosis.

Further evidence suggests that both PI3K and PIM kinase are involved in immune cell regulation, actively promoting and protecting cancer cells. PIM kinase isoforms defend cancer cells from therapeutic and immune attacks (E. Morales; Apoptosis; September 2016) while PI3K controls immune suppression (Vanhaesebroek; Cancer Discovery; October 2016). Inactivating both these pathways would complement the growing immunotherapy approaches (e.g. PD-1, PD-L1) which are becoming standard of care in a number of cancers.

Our approach is to achieve superior clinical effect by harnessing the power of PI3 kinase inhibition to slow tumour cell growth and combine it with PIM kinase inhibition that blocks the escape pathway for signalling in the cancer cells. This dual mechanism has the advantage of being more effective in arresting tumour cell growth, driving cancer cell death and preventing the emergence of the resistance that has been observed with PI3K inhibitors in the clinic.

Our pipeline

Our dual mechanism approach inhibits both PI3K and PIM kinases without affecting other kinases. The IBL-300 series are PIM/PI3k/mTOR inhibitors and our IBL-200 series are PIM/PI3k inhibitors. The macrocyclic chemistry underpinning our dual mechanism inhibitors confers a strong patent position and we have a granted composition of matter patent covering our molecules.

Our lead molecule, IBL-302 is our first-in-class oral kinase inhibitor rationally designed to uniquely combine pan-PIM kinase, pan-PI3K and mTOR inhibition in a single agent. The data for IBL-302 indicates potent efficacy, good tolerability and favourable drug properties. IBL-302 has been tested in over 700 cell lines with activity shown across a broad range of tissue types. Initial analysis of this cell line panel identifies PIK3CA mutation, high PIM kinase expression and elevated MYC expression as factors indicating sensitivity to IBL-302, markers which may be supportive in selecting patient subgroups in clinical trials.

We have now generated a pre-clinical data package on IBL-302 which supports the commencement of IND enabling studies. This includes proof-of-concept in several xenograft models and in patient tissue samples with the data suggesting utility in both haematological malignancies and solid tumours, especially breast cancer.

Breast cancer

Approximately one million people globally are diagnosed with breast cancer each year and, of these, one third have a mutated PI3K pathway. Additionally, PIM kinase expression is elevated in triple negative breast cancer tumours and is associated with poor prognosis in patients with hormone - and HER2-negative tumours (A Goga; Nature; October 2016).

Researchers at the Dana Faber Cancer Institute sought to understand what may be driving resistance to PI3K inhibitors in breast cancer. They noted that high PIM expression confers resistance and so co-targeting of PIM kinase and PI3K may be warranted in a subset of breast cancers (L. Garraway; Cancer Discovery; October 2016).

As a result of our proof-of concept data with our dual mechanism program, we have established a research collaboration with the Royal College of Surgeons of Ireland (press release) to refine the potential clinical setting in breast cancer for IBL-302, specifically in treatment-resistant breast cancer, including triple negative breast cancers.

Indication Expansion

Beyond our lead target indication in breast cancer, we also see potential for IBL-302 in other cancers including lung cancer, AML, lymphoma and pancreas cancer.

Better patient convenience and lower development costs

Our dual approach, single tablet combination, has enormous potential advantages across the cycle from development costs to patient convenience. Combining experimental agents into a single dose will be less expensive than developing two separate drugs and less costly for patients too. It also makes prescribing and patient compliance more straightforward as physicians only need manage a single side effect profile.

Poster Presentations:

"Evaluation of dual-acting PIM/PI3K inhibitor IBL-302 in preclinical breast cancer models"

2018 American Association for Cancer Research (AACR) Annual Meeting, April 14-18, 2018 in Chicago. Link to abstract here.

“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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