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    Home > Biochemistry News > Biotechnology News > Flt3 inhibitor AML produces CR: talk about off-target activity

    Flt3 inhibitor AML produces CR: talk about off-target activity

    • Last Update: 2021-04-27
    • Source: Internet
    • Author: User
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    Today Aptose Bioscience announced that its multi-kinase inhibitor Luxeptinib (formerly known as CG-806) produced a complete response in the early clinical stage of an acute myeloid leukemia (AML).
    This phase I/II clinical is expected to recruit 80 patients, the main purpose is to study the side effects and tolerable dose of the drug in this population.
    This case of CR appeared in the 450 mg twice a day group, but no other information was released.
    Because AML is the worst-controlled hematological tumor, CR is not common, affected by this news, APTO today rose by 60%.

    Drug source analysis

    Drug source analysis

    Luxe was originally developed as a reversible BTK inhibitor and its main use is chronic leukemia, but so far it is still a substitute goalkeeper in this arena.
    BTK inhibitors are an important breakthrough in chronic leukemia, but the main drugs are covalent inhibitors, and there are some theoretical problems.
    The first drug Imbruvica was originally a so-called tool compound for screening compounds, but it was developed into a blockbuster drug by Pharmacyclic.
    Half of the equity in this product was acquired by Johnson & Johnson for US$1 billion, and the other half was acquired by Abbott for US$21 billion a few years later.
    It can be seen that even after clinical confirmation, many people have greatly underestimated the potential of this product.

    One potential problem with covalent compounds is the so-called off-target side effects.
    Small molecule drugs bind to the target through intermolecular interactions.
    In order to avoid binding to incoherent targets, drug design usually adopts a multi-point weak binding strategy based on the characteristics of the target binding cavity, so that only when all molecular fragments are present.
    Will combine.
    Covalent compounds rely on a main warhead, and other fragments only play a secondary role.
    The advantage of this kind of star tactics is that it does not require much work to optimize the auxiliary clips.
    The price is that the warhead is often too self-expanding and combines with many targets.
    Although covalent drugs have existed since ancient times, the recent great success of kinase inhibitors such as EGFR and BTK inhibitors has made everyone basically ignore the potential dangers of this strategy.

    But even patients with off-target side effects of serious diseases such as tumors sometimes can't bear it, and Luxe came into being.
    Unfortunately, Luxe, like other reversible BTK inhibitors, did not show any advantages in chronic leukemia, but found a second spring in AML.
    The irony is that this effect comes from off-target side effects that Luxe originally wanted to avoid.
    This effect will not be due to the inhibition of BTK, but Flt3.
    Flt3 variants are common in AML (~30%), and several Flt3 inhibitors have been marketed for AML.
    But what is even more ironic is that from the structure of these compounds, they are likely to inhibit other kinases in addition to Flt3.
    In particular, the first drug midostauline is a direct relative of the kinase bully staurosporine.
    It is hard to imagine how the selectivity will be better, so It's hard to say who the real target is.
    Flt3 is a cytokine receptor kinase that plays an important role in normal immune cell renewal.
    Its ligand Flt3L has recently been used to attract dendritic cells into TME to strengthen the immune response.

    Off-target activity is one of the main differences between small molecule drugs and biological drugs.
    Although unexpected gains like today occur from time to time, off-target activity more often brings disasters.
    Half of the clinical failures of small molecule drugs are due to lack of specificity, which is also the most worrying place.
    No one can guarantee that there will be no scandals and accidents after the market is not over.
    Poor selectivity also makes the molecular mechanisms of many drugs ambiguous, and the development process mainly depends on guessing.
    For example, Pfizer’s main blockbuster drug Lyrica was originally designed as a gamma-Martinate transaminase inhibitor, but it was later discovered that activating glutamate decarboxylase activity was the source of animal curative effects, and then the real reason was to block a calcium ion channel.
    Merck’s blockbuster drug Zetia was originally developed as a cholesterol acetyltransferase inhibitor, but it was later discovered that the curative effect comes from inhibiting cholesterol absorption.
    Although the target of another type of heavier drug statin is correct, the inhibition of HMGCoA reductase does not inhibit cholesterol synthesis.
    Because the negative feedback mechanism will increase the expression of this enzyme, what really works is the internalization of the LDL receptor.
    However, kinases are the hardest hit area for off-target activity due to their numerous family members and highly consistent appearance.
    Comparing to kinases, they are central drugs.
    For example, recent studies have found that depression drugs such as Prozac act through the receptor kinase TRKB.

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