The Dilemma and Outlet of Small Molecule Drugs

To this day, I still clearly remember that when I applied for graduate school to choose a major, I chose medicinal chemistry very resolutely.

1

The Dilemma of Small Molecule Drugs-"A Wolf and a Tiger"

Looking back at the sales data of innovative drugs in the past 20 years, we found that in 2000, 8 of the top 10 innovative drugs in global sales were small molecule drugs.

Small molecule drugs ranged from morphine in poppies and salicylic acid in willow trees to the first "blockbuster" drug with annual sales of more than $1 billion in history-diazepam in the last century, to the first in 2001 Gleevec, a small-molecule drug targeting specific gene mutations in cancer cells, and now more than 60 small-molecule kinase inhibitors have been approved.

To explore the dilemma of the development of small molecule drugs, we first need to understand the most important basic method of modern small molecule drug development-Screening.

From the end of the last century to the beginning of this century, the rapid progress of small molecule drug research and development largely relied on the discovery of new disease targets and disease indications, the explosive development of organic synthetic chemistry and the progress of various detection technologies.

2

Game

Driven by the huge pharmaceutical market and a strong sense of social responsibility, major global economies are doing their best to develop the biomedical industry.

Compared with biotechnology such as large molecule antibody drugs, the advantages of small molecule drugs:

(1) Most small-molecule drugs can be taken orally and are convenient to administer.

(2) Small molecule drugs can act well on intracellular (including nuclear targets) and extracellular targets.

(3) Some small molecule drugs can pass through the blood-brain barrier and can be used for the treatment of brain diseases.

(4) The sensitivity of small molecule drugs to the storage environment is relatively low, and storage and transportation are convenient.

(5) There is almost no immunogenicity.

(6) Small molecule drugs are relatively easier to achieve differentiation, which benefits from the numerous and relatively mature targets of small molecule drugs.

Compared with biotechnology such as large molecule antibody drugs, the disadvantages of small molecule drugs:

(1) It is difficult to develop targets without suitable action pockets.

(2) The specificity is not high.

(3) The half-life is short, and it often needs to be taken once a day or even multiple times a day.

(4) The development success rate is low.

(5) The preparation process is relatively simple and mature.
This is both an advantage and a disadvantage.
The relatively simple and mature preparation process makes the production cost of small molecule drugs far lower than other biotech products.
At the same time, it is a relatively simple and mature preparation process.
When the patent for a small molecule drug expires, Generic drugs can seize the original research market at a relatively low cost, creating a "patent cliff" for small molecule drugs.

Small molecule drugs are the most traditional form of drugs.
Although the current development has encountered some difficulties, it also has its advantages that are difficult to replace.
ADC, cell therapy, gene therapy and other new drug forms are gradually emerging, showing their unique advantages and amazing potential in multiple therapeutic fields, but at the same time they are also facing their own severe challenges.
I believe that there will be multiple in the near future.
In a competitive landscape where drug forms coexist, followers of various therapies will also strive to seek breakthroughs in their own fields.

3

The way out for small molecules—

"Grow a small wing, you can fly higher"

"A pig can fly when standing on a wind vent" actually has the second half-"If you grow a little wing, you can fly higher.
" Small molecule drugs are once "a pig at the forefront".
Although the current development has encountered difficulties, as long as new breakthroughs are made at certain key points and a small wing is added to myself, I think the future of small molecule drugs can of course be Higher and farther.
With the rapid development of molecular biology and structural biology, small molecule drug discovery has entered the era of target-based drug design.
We can perform high-throughput screening based on a target and obtain composite crystals of small molecules and target proteins.
The structure is rationally optimized with the aid of a computer, and the research and development of drugs has become so clear.
High Throughput Screening (HTS), Virtual Screening (Virtual Screening), Structure-based Drug Design (SBDD) and Fragment-based Drug Discovery (FBDD) have gradually become small molecules Common techniques for drug development.
These technologies have achieved great success and are still being continuously enriched and developed.
However, the efficiency of small molecule drug discovery has not improved as much as people expected.
In recent years, many new ideas have emerged in the field of small molecules and new breakthroughs have been achieved.
The editor believes that small molecules may achieve breakthroughs in the following areas: PROTAC technology, molecular glue, allosteric regulation, and new use of old drugs.

1.
PROTAC technology

PROTAC (Proteolysis Targeting Chimera, protein degradation targeting chimera) is a bifunctional small molecule, which is obtained by linking the target protein ligand and the E3 ubiquitin ligase ligand through Linker, and uses the ubiquitin-protease system to recognize, bind and degrade diseases Related target protein.
This technology was first proposed by Raymond Deshaies and others in 2001.
In theory, it can eliminate any over-expressed and mutated disease-causing proteins to treat diseases.

In fact, some drugs have been accidentally discovered to have the effect of degrading target proteins in clinical practice: for example, the breast cancer treatment drug Fulvestrant can degrade estrogen receptors; lena polyamine can specifically degrade the transcription factors IKZF1 and IKZF3; the third generation The EGFR inhibitor osimertinib can also selectively induce the degradation of EGFR-T790M.
These unexpected discoveries are not universal, and it is difficult to obtain them through reasonable design.
PROTAC, as a subjectively designed small molecule that degrades target proteins, has made amazing progress in the field of tumors and autoimmune diseases.
It has also shown great potential in the treatment of "non-drugable targets" and the treatment of resistant patients with current therapies.
Having been widely recognized by the scientific community and the capital market, many PROTAC companies have now landed on Nasdaq, and many multinational pharmaceutical companies have also actively participated in the layout of the track, and have reached a number of blockbuster cooperation agreements.
PROTAC technology wears a "star halo" and whether it can lead the rise of small molecule drugs again depends on the clinical progress of related products in the next few years.

2.
Molecular glue

Molecular Glues are a class of small molecule compounds that can induce or stabilize the interaction between proteins.
When one of the protein molecules is ubiquitin ligase, molecular glue can cause another protein to undergo ubiquitin modification and degradation through the proteasome pathway, which is similar to PROTAC.
Classical molecular gel degradation agents such as thalidomide analogs and arylsulfonamide anticancer drug Indisulam, etc.
, all use the complementary protein-protein interface between E3 ubiquitin ligase and target protein to reprogram the ubiquitin connection The selectivity of the enzyme drives the ubiquitination of the target in a catalytic manner.
Therefore, molecular glue also cleverly avoids the limitations of traditional inhibitors, making some of the targets change from "non-druggable" to "druggable".
At the same time, molecular glue has a smaller molecular weight than PROTAC, which theoretically will Have better medicinal properties.
The molecular glues discovered in the early stages are mostly accidental.
In recent years, the molecular glues actively designed have also made good progress.
In November 2020, Eli Lilly and Wanchun Seed, a subsidiary of Wanchun Pharmaceuticals, completed a cooperation agreement with a total value of 790 million U.
S.
dollars.
They will develop new drug candidates with the help of Seed's proprietary proprietary molecular gel protein degradation technology.
In December 2020, Neomorph, a molecular glue technology company, announced the completion of a US$109 million Series A financing to promote the development of a proprietary targeted protein degradation platform and related projects.
In the same month, Boehringer Ingelheim also has a layout in the field of molecular glues and signed a cooperation and licensing agreement with Proxygen to jointly develop molecular glue degradation agents that target multiple carcinogenic targets.
In March 2021, Monte Rosa Therapeutics announced the completion of a $95 million Series C financing to promote its main molecular glue products into the clinic, accelerate pipeline development and enhance platform capabilities.

3.
Allosteric regulation

Allosteric Regulation (Allosteric Regulation) specifically affects protein conformational changes, thereby stabilizing it in an inactive or activated state, which is different from traditional substrate-competitive inhibitors such as ATP-competitive kinase inhibitors.
There is an interesting "fat man theory" in allosteric regulation.
Taking the design of kinase inhibitors as an example, kinase substrates such as ATP bind tightly to the active center of the enzyme, just like a fat man sitting on a chair.
Traditional competitive inhibitors need more strength, that is, higher affinity, to pull this fat man up.
On the other hand, the allosteric inhibitor pierced a nail somewhere in the chair, and the fat man jumped up on his own without much effort.
Allosteric regulation not only has better selectivity, safety and the potential for overcoming drug resistance because of its unique mechanism of “four-two shifts”, it can also make some targets change from “drugless” to “drugged”, causing Has attracted the attention of many scientific research institutions and pharmaceutical companies.
With the development of structural biology, the identification of allosteric sites has become relatively easy, which has further promoted the development of allosteric regulation of small molecule drugs.

Novartis’s BCR-ABL1 allosteric inhibitor Asciminib binds to the myristoyl site (non-ATP structural site) of the BCR-ABL1 protein, and locks BCR-ABL1 to none through a mechanism different from other BCR-ABL1 kinase inhibitors.
Active conformation.
Asciminib is used in a phase 3 clinical trial of patients with chronic myeloid leukemia (CML) who have received two or more tyrosine kinase inhibitor (TKI) treatments and have developed resistance or intolerance to the most recent TKI treatment The primary clinical endpoint was reached in the preliminary analysis, and the FDA recently obtained 2 Breakthrough Therapy qualifications.
The relatively hot KRAS inhibitors (such as AMG510, clinical phase III, which has been submitted for marketing in the past two years) and SHP2 inhibitors (TNO155, clinical phase II) are allosteric inhibitors of the corresponding target, and they are all "non-drugable targets.
"Point" great breakthrough.

4.
New use of old drugs

"The best way to discover a new drug is to start with an old one", which was put forward by pharmacologist James Black, winner of the Nobel Prize in Physiology or Medicine in 1988.
In short, it is "the new use of old drugs.
" "Old drugs" refer to drugs that are already on the market or drugs that are undergoing clinical trials, and "new use" refers to the discovery of the use of these drugs in new indications.

Aspirin was invented in the United States in 1899.
It has been used as an antipyretic and analgesic for more than a hundred years.
With the continuous deepening of clinical research, many new effects and new effects of aspirin have gradually been discovered, especially in the prevention of cardiovascular diseases.
And the role in treatment.
The "Chinese Cardiovascular Disease Prevention Guidelines (2017)" began to use low-dose aspirin as the basic drug for cardiovascular disease prevention.
The infamous thalidomide is also a classic case of new use of old drugs.
Thalidomide (trade name: thalidomide) was successfully marketed in Europe in the 1950s and caused tens of thousands of people worldwide in just a few years.
The case of neonatal malformation (sea leopard fetus) became one of the biggest tragedies in the history of the drug, which forced the drug to be delisted in 1963.
In 1964, when doctors used it to leprosy patients, they unexpectedly found that thalidomide could effectively alleviate the patients' skin symptoms.
In the 1990s, anti-inflammatory and anti-tumor effects were successively discovered.
In 1998, Thalidomide was approved by the FDA for the treatment of multiple myeloma.
Sildenafil (trade name: Viagra) was originally developed to expand cardiovascular smooth muscles to expand blood vessels to treat angina pectoris, but the effect is not satisfactory.
With the same mechanism of action, it has been clinically found to have very relaxing effects on the smooth muscles of the corpus cavernosum.
Significantly.
In 1998, the FDA officially approved sildenafil for the treatment of erectile dysfunction.

In the past few decades, like aspirin, thalidomide, sildenafil and other drugs, there have been many successful cases of "old drugs" changing their uses into "new drugs", bringing immeasurable results to patients and pharmaceutical companies.
Benefit.
In the 2020 novel coronavirus pneumonia epidemic, "old medicines and new applications" also played an important role.
The new crown epidemic came very suddenly, and it is obviously too late to design and obtain a brand new anti-coronavirus drug to control the epidemic.
In addition to stepping up research and development of the new crown vaccine, there are also many scientists who hope to screen from the existing marketed or late-stage clinical compounds to find potential new crown treatment drugs.
Antimalarial drugs such as hydroxychloroquine, antiviral drugs such as lopinavir, ritonavir, ribavirin, etc.
, including "people's hope"-Redecive have all carried out clinical trials for the new crown.
The US FDA announced on May 1, 2020 that it granted Remdesivir Emergency Use Authorization (EUA) to treat COVID-19 patients.
Although the final treatment effect was not so ideal, it also played a certain role in preventing the further deterioration of the global new crown epidemic.
Positive effect.

4

Outlook

In terms of relatively mature technologies such as deuterated drugs, covalent inhibitors, and peptide drugs, small molecule drugs are also likely to usher in breakthroughs.
With the continuous maturity of artificial intelligence (AI) technology and the continuous penetration of new drug research and development, artificial intelligence in the discovery of targets, the discovery of seed compounds and lead compounds, the design of drug molecular synthesis routes, the establishment of disease models, and the discovery of new indications, etc.
In terms of assisting the research and development of new drugs, it will greatly improve the research and development efficiency of new drugs.
Recently, AI pharmaceutical giants have joined forces.
Roivant intends to acquire Silicon Therapeutics for US$2.
05 billion (down payment of US$450 million + milestone payment); domestic Internet giants BAT (Baidu, Ali, Tencent) have also invested a lot of energy in active deployment of AI drugs in recent years It is found that it is believed that both small-molecule drugs and large-molecule drugs can usher in an opportunity for vigorous development with the help of artificial intelligence technology.
Small molecule drugs have their irreplaceable advantages.
Its development is also a history of alternating dilemmas and breakthroughs.
With the continuous emergence of various new technologies, we also look forward to more "black technologies" to help the research and development of small molecule drugs.
The breakthrough brought more surprises to the world.

Be brave to be the protagonist and willing to be a supporting role Small molecule drugs have always played the "protagonist" in the history of drug development.
As various biotechnology therapies become more abundant and mature, the treatment of diseases will inevitably show a trend of blossoming.
In recent years, combination medication has gradually become the development trend of clinical trials, especially the rise of tumor immunotherapy, which has further promoted the attempts and breakthroughs of combination medication programs.
I think in the future, small molecule drugs will still be the "protagonist" in some disease fields.
In other fields, small molecule drugs may really be gradually replaced or eliminated.
In more fields, small molecule drugs and biotechnology therapies will be used.
"Strong unity", so as to better solve problems for patients.