sPLA₂

• Secreted phospholipase A2 (sPLA₂) is an enzyme identified in the 1980s as a critically important player in inflammation, acting as the major funnel between inflammatory triggers (cytokines) and the eventual inflammatory response
• That role marked sPLA₂ as a major drug target for the treatment of acute inflammatory diseases such as asthma and chronic inflammatory/ autoimmune diseases such as rheumatoid arthritis and psoriasis
• After considerable effort, anti-sPLA₂ drug development eventually was abandoned in the late-1990s/early-2000s because of serious safety concerns. Attention then shifted to blocking the upstream triggering of sPLA₂ by pro-inflammatory cytokines. This led to the development of major drugs (TNF-a inhibitors) such as Humira and Remicade
• As successful as anti-cytokine antibody drugs have been, their limitation is that more than one pro-inflammatory cytokine is involved in inflammation, leaving sPLA₂ as the obvious drug target because of its non-selective response to all cytokines.

hGIIA

• Toxicity and efficacy issues associated with earlier sPLA₂ inhibitors are now known to be stem from sPLA₂ not being a single entity as originally believed, but 9 different sPLA₂ sub-types
• All 9 sub-types display different functions depending on the type of inflammatory response, a heterogeneity that proved an insurmountable barrier to earlier drug developers taking a one-size-fits-all approach
• That barrier is potentially now overcome with a single sub-type, hGIIA, now recognized as the primary sPLA2 sub-type driving inflammation associated with cancer development, acute inflammation (eg, asthma), chronic inflammation (eg, arthritis) and heart disease. hGIIA also is involved in how viruses such as coronaviruses enter cells
• hGIIA levels are elevated in a wide range of cancer types such as lung, ovarian and prostate cancers and melanoma
• In prostate cancer, high hGIIA levels are associated with more advanced disease and poorer survival outlook, making hGIIA an obvious drug target as a treatment for advanced prostate cancer

_{Confocal microscopic video of sPLA2 moving around the vimentin cytoskeleton in a prostate cancer cell}

FLM-c2

• FLM-c2 is a selective inhibitor of hGIIA
• FLM-c2 is the first and only selective hGIIA inhibitor known to have reached the clinic
• A key function of FLM-c2 is to block the ability of hGIIA to bind to vimentin in cancer cells, an important function with vimentin being a key driver of cancer metastasis
• FLM-c2 has successfully undergone a Phase 1a study in 12 prostate cancer patients, proving to be well tolerated

The Tribbles 2 (Trib2) gene has emerged in recent years as a potentially major drug target because of its diverse and important roles in germ cell development, reproduction, innate immunity and inflammation - a diversity that has led to abnormal Trib2 activity being implicated in a range of neurological disorders, metabolic diseases, cardiovascular disease (atherosclerosis), autoimmune and inflammatory diseases, and cancer.

To date, no Trib2 inhibitor has been developed, leaving the broad field of diseases associated with abnormal Trib2 activity largely unexplored.

Trib2 is believed to promote cancer in a number of key ways:

1. By transforming cancer cells into a more aggressive form known as a neuro-endocrine phenotype
2. By blocking the ability of the local innate immune system (macrophages, monocytes) to mount an anti-cancer immune response
3. By making the cancer cells more resistant to drugs.

An international collaboration led by the Henry Ford Cancer Institute recently identified over-activity of Trib2 as being behind the loss of effectiveness of a class of drugs known as androgen receptor inhibitors in prostate cancer. Drugs in this class provide the last effective barrier to progression of prostate cancer into a lethal disease and extending their effectiveness is a major unmet need.

FLM-JG1

A Trib2 inhibitor being developed for use in combination with androgen receptor inhibitors

FLM-JG1

• In the absence of a drug that blocked Trib2 activity, the Henry Ford scientists screened libraries of molecules, finally identifying an existing drug, daclatasvir, as a potent Trib2 inhibitor
• Daclatasvir is an anti-viral drug released to the market in 2014 as a treatment for hepatitis C infection, but subsequently withdrawn when more effective drugs came to market
• Daclatasvir proved to be highly effective in the laboratory at reversing the resistance of prostate cancer cells to drugs such as enzalutamide
• Daclatasvir is being repurposed as FLM-JG1 as an anti-cancer drug, with the purpose of extending the effectiveness of drugs such as Xtandi, Zytiga and Erleada in patients with advanced prostate cancer

FLM-BT2 blocks cancer cell growth

FLM-BT2 binds to a key enzyme called MEK and prevents it activating another enzyme called ERK that regulates gene expression and drives tumour invasion and cancer growth.
(Image from Govender and Chetty J Clin Path 2012;65,986-988).

FLM-BT2 is anti-inflammatory

FLM-BT2 also blocks the ERK-FosB/ΔFosB-VCAM1 axis resulting in inhibition of:

• new blood vessel formation (angiogenesis),
• leaky capillaries (vascular permeability)
• the production of pro-inflammatory cytokines and other cell surface adhesion molecules.

FLM-BT2 is a novel immuno-oncology drug

FLM-BT2 inhibits a critical immune checkpoint protein called PD-1 found on immune cells such as T cells. Blocking PD-1 on T cells allows the immune system to more effectively attack and destroy cancer cells.

(Image from Chi et al. Cell Mol Life Sci 2021;78,3239–3246).