Other Inhibitor Drugs

Biologists call Signal Transduction Inhibitors any compound that blocks chemical signals from cell to cell.  Most of the signal transduction inhibitors made into drugs effective in clinical use are kinase inhibitors. Other methods provoke the ongoing interest of scientists:

FLT3 inhibitors

Cats can get a cancer called Feline McDonough Sarcoma and it was when studying this that scientists identified an oncogene – which occurs in humans too – that is associated with dysregulation of a type of receptor tyrosine kinase.   This fms-like tyrosine kinase 3 (FLT3) plays a key role in creation of new blood cells and hence is of interest to doctors looking into leukemia. FLT3 inhibitor drugs have been developed in an attempt to fight leukemia.

Only one FLT3 inhibitor is on the market.  Midostaurin was approved for acute myeloid leukemia, but the label says the AML should be FLT3-positive.  In other words, an analysis of the malignant blood cells should show a mutation of the FLT3 gene. But that’s still a big number of potential patients because 30 percent of AML cases test positive for this mutation.

Two other FLT3 inhibitors are in the advanced phases of trials and may be nearing approvals. Quizartinib was designated for breakthrough status by the FDA in August 2017, based on some good results.  This is a positive sign for ultimate approval of the drug someday.

Gilteritinib has been granted orphan drug status by regulators in the US, Japan, and Europe, and was approved for fast-track status by the FDA in 2017.  Its developer applied for full approval in Aug 2018.

Proteasome inhibitors

Proteasomes are physiological micostructures that are part of the body’s waste management system.  They break down old and unneeded proteins that the cells need to be rid of. Compounds that stop or slow the action of the proteasomes are called proteosome inhibitors and scientists are looking at them as ways to fight cancer.  Some work so well they have gone through the drug development process and are approved for use against multple myelona. myeloma, mantle-cell lymphoma (MCL) and amyloidosis

Proteosome inhibitors have names that end in “zomib”

Ixazomib
Carfilzomib
Bortezomib

See also: Overview of Proteasome Inhibitor-Based Anti-cancer Therapies

PI3K Inhibitors

PI3K is a class of enzymes that are classified as lipid kinases.  All kinases promote phosphorylation of chemicals in the cell, but lipid kinases specifically promote phosphorylation of lipids.  Cell membranes are rich in lipids. The PIK3 enzymes are important signal transducers and work (among elsewhere) in transmission of signals across the cell membrane.  There are many enzymes that could be considered PIK3 ones, and biologists have further divided them into threes classes: PI3Ks (I – III).

Scientists have found small molecule drugs that can stop the action of the enzymes.  These are called Phosphatidylinositol 3-kinase inhibitor or phosphoinositide 3-kinase inhibitors but almost always designated by the abbreviation PI3K inhibitors.

Only three PI3K inhibitors have been approved by the FDA for treatment of cancer, and all of these came on the market only in the past few years.  Idelalisib, Copanlisib and Duvelisib were all approved for lymphoma. Once enough patients have undergone treatment, doctors may be able to form a general opinion of this drug class.  The PI3K inhibitors are often given in combination with other chemotherapy agents.

Research continues in this field – clinical trials of PI3K inhibitors are going on right now.  Because The PI3K pathway gets messed up in an estimated one out of three cancers in humans there is hope this class of drugs will eventually prove effective in treatment of other types of cancer besides lymphoma.

Notch inhibitors

It is known that some genes cause or contribute to the initiation and/or growth of cancer, and one are of research is whether blocking the action of those genes can stop or prevent the cancer. The Notch gene was first found in 1917 and now it turns out that the gene is implicated in a signaling system that is part of tumor growth.

Cell membrane surfaces have receptors now referred to as Notch receptors. In scientific literature there are referred to as Notch1 (or more formally Notch homolog 1 translocation-associated receptor), Notch2, Notch3, and Notch4.

A bunch of potential notch inhibitors are being investigated for their effects on cancer proliferation. There is an interest in combining them with hedgehog inhibitors. Cancer stem cells – aka tumor-initiating cells – are an area in which scientists think notch inhibitors might be helpful. However, Nature reports that work done to date has found no substantial antitumor effect of notch inhibitors.  There are no notch inhibitor therapies in clinical use at this time.

Consequences of Disrupted Notch Signaling in Bladder Cancer.

Molecular pathways: translational and therapeutic implications of the Notch signaling pathway in cancer.

NOTCH pathway inactivation promotes bladder cancer progression.

NOTCH Decoys That Selectively Block DLL/NOTCH or JAG/NOTCH Disrupt Angiogenesis by Unique Mechanisms to Inhibit Tumor Growth
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Changes in the regulation of the Notch signaling pathway are temporally correlated with regenerative failure in the mouse cochlea
.

Notch inhibitors for pulmonary arterial hypertension – SciBX Science Business Exchange

Notch inhibition reverses kidney failure – Nature

PARP Inhibitors

PARP Inhibitors (PARPi) are a promising group of drugs with a wide potential as sensitizers for chemotherapy and radiotherapy.

 

Hedgehog pathway inhibitors

The Hedgehog signaling pathway transmits signals to cells and tells them what kind of cells to turn into.  When an embryo develops cells must differentiate so the organism can have different organs and function as a multi-cellular organism.  Biologists name subtypes the Desert, Indian, and Sonic pathways. Even after the baby is born, there is still a Hedgehog signaling pathway.  In adults, the pathway sometimes becomes activated leading to (or somehow being associated with) the proliferation of malignant cells. The stem cells present in the body are converted to cancer cells.  Scientists are still trying to figure it all out, but there is evidence that activation of the Hedgehog pathway occurs in initiation and growth of several types of cancer, including basal cell carcinoma.

The oral drugs Sonidegib and Vismodegib are on the market and approved for basal cell carcinoma.

Itraconazole has been used as an anti-fungal medication and scientists found it works in disrupting the hedgehog pathway.  It has therefore sparked interest by scientists who see an opportunity to repurpose it as a cancer medicine.  Clinical trials are underway to look into itraconazole for melanoma positive for the BRAF V600 mutation and for basal cell cancer.

Vismodegib

Sonidegib

SignalTraducerInhibitors