Protein degradation, other inhibition: small molecule drug make-up

Protein degradation pioneer Arvinas today announced the clinical advances of its estrogen, androgen-recessed degradation drugs ARV-471 and ARV-110 in the first phase of breast and prostate cancer.
ARV-471 produced 1 confirmed PR, 2 unrefirmed PR and 2 SDs in 14 patients who were ER-positive and received an average of 5 treatments, with an average degradation of 62% of ER recipients.
ARV-110 reduced tumors by more than 50 percent in 28 patients who progressed with an average of five drugs, including two patients with rare AR mutations.
both drugs were well-resistant and had no toxic reactions above level 3.
ALVN has doubled as a result of this message.
today Roche also announced that it will retain the development rights for Relay's SHP2 structure inhibitor, RLY-1971, in association with its kras inhibitor GDC-6036, with a down payment of $75 million, and that Relay will retain the development rights for RELY-1971 and other drug complexes.
investors were not happy with the deal, with Relay down 10 per cent.
analysis rational protein degradation and other structure inhibitors are now small molecules of new drug research and development of pre-drug technology.
are not completely new technologies, but they are now more controllable and rational.
androgens play an important role in the growth of some breast and prostate cancers, and traditional antagonists also induce the degradation of the subject.
such as fluorovis groups can also degrade to 50% ER, compared to 62% of ARV-471 is not the difference between day and night.
the same AR antagonist drug also degrades AR.
also have multiple drugs on the market, such as many central drugs, but they are all a coincidence.
now companies such as Relay and Arvinas are systematically, systematically designing and developing these new drugs that are different from traditional enzyme inhibitors and positive regulators for the subject.
ASCO has released some data this year, and today's stock market reaction is mainly arv-471.
these patients have been treated with CDK-4/6 inhibitors and a variety of ER antagonists, including other clinical protein degradation drugs.
so 42% of patients benefit from this new technology, with fewer side effects.
but there are still some problems with this data if it's broken.
first of all, the effect of degradation ER is not obvious, the largest reduction of a patient with a minimum dose of 30 mg, of course, there are many reasonable explanations.
is that the ARV-471 has not degraded much more ER than antagonists.
is that most CDK4/6 inhibitor progression patients belong to ER non-dependent resistance, degradation ER effective may be unrelated to the mating activation path.
if you look at these functions ER is not yet a confirmed target, also does not rule out that E3 to ER near hand-in-hand sheep degradation of other important proteins, or is inhibiting E3 played a role.
of course, if it works, no one cares, the problem is that if the effect is not from ER degradation, the clearest understanding of the mechanism of the drug's future performance is not predictable.
after all, both functions of PROTAC may have a certain tumor control effect.
inhibitors are a key technology to deal with non-drug targets, relying on the combination of drugs and some hydrophobic cavities on the protein surface indirectly reduces the binding capacity of positive composition binding cavities and natural receptors.
SHP2 is a non-drug target, and a few years ago Novaral used a clever screening technique to find a very simple, efficient, high-class drug-like other-structure inhibitors, making this target a drug-ready target.
SHP2 upstream of KRAS is a phosphatase that helps SOS load GTP for Kras, and inhibiting SHP2 strengthens the efficacy of KRAS inhibitors.
Roche has a G12C inhibitor, but is now far behind amSeon's upcoming AMG510.
and KRAS inhibitors are only possible in lung cancer response rates, but the response time is not long-lasting, in another major solid tumor CRC response rate is very low.
so it is possible to use SHP2 not only to expand the adaptive disease, extend the response time, but also to occupy a more favorable position in the combination market competition.
small molecule drugs face the squeeze of antibodies, RNA, gene therapy and other new therapies, its lower selectivity is a fatal defect.
but the oral advantages, costs and compliance advantages of small molecular drugs can not be ignored, if left from the traditional positive structure of the comfort zone has a great future.
these two events today are good footnotes.
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