January 17, 2022

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19 milestone targets of human diseases in 2021

19 milestone targets of human diseases in 2021

19 milestone targets of human diseases in 2021

19 milestone targets of human diseases in 2021. 

Identifying better targets is one of the key challenges facing drug development today.

Since the 1990s, the pharmaceutical industry has developed a variety of drugs that change the treatment of cancer and other diseases through the target-based drug discovery (target-based drug discovery, TDD) model.

Therefore, scientists and drug developers around the world have discovered targets The aspect has always maintained active investment.

Who is the next PD-1? Who is the real effective AD target that can replace Aβ? Who is the strength target that is expected to solve the global obesity problem? Medical scientists are always looking for answers to these questions. These answers are also the key to achieving the next medical breakthrough.

In 2021, scientists have achieved many important results in the discovery of new targets.

For example, in terms of anti-cancer, multiple milestone targets have emerged, such as ID3, SOX4, CLIP1-LTK, DDR1, GABA A receptor, COP1 , METTL3, CD161, NSD3, neutrophilelastase, etc., among which DDR1 was published on the same day as the paper.

Related companies It also announced the completion of a US$65 million Series A financing.

Among the investors is the giant Pfizer. The team of CAR-T pioneer Professor Carl H. June also found two important new targets for CAR-T treatment of solid tumors this year— —ID3 and SOX4; GABA A receptor has attracted much attention from the field of neurological diseases to the field of cancer…

In terms of obesity problems, scientists have identified key targets such as IL-27 and GPR75. Among them, GPR75 was “fancy” by AstraZeneca less than one month after the paper was published, and reached a cooperation with Regeneron.

In addition, in the past year, Alzheimer’s disease, NASH, diabetes, aging, cardiovascular disease, atherosclerosis, amyotrophic lateral sclerosis, chronic obstructive pulmonary disease, bacterial infection, pain and other disease fields There are also new developments in target discovery.

At the end of the year,  experts sorted out and screened out 19 milestone new target from  the 100 most noteworthy new target-related studies in 2021, hoping to provide some references for innovative drug developers and investors.

Milestone target①: ID3, SOX4

  • Magazine: Cell
  • Field: Cancer, CAR-T
  • Paper: https://doi.org/10.1016/j.cell.2021.11.016


In a study published in Cell on December 2, a team of scientists from the Perelman School of Medicine at the University of Pennsylvania revealed the key molecular mechanism of the CAR-T depletion process and pointed out potentially effective strategies to overcome the depletion process , Brings new hope for CAR-T treatment of solid tumors.

In the study, Professor Carl H. June and his colleagues discovered that the genetic regulatory factors ID3 and SOX4 play a key role in the process of T cell exhaustion, and silencing these two factors greatly enhances the tumor-killing effect of CAR-T. ( Recommended reading: Daniel Carl June’s latest Cell: CAR-T treatment of solid tumor key new targets-ID3 and SOX4 )

Milestone target ②: B4GALT1

  • Magazine:Science
  • Field: Cardiovascular Disease
  • Paper: DOI:10.1126/science.abe0348


Elevated levels of low-density lipoprotein cholesterol (LDL-C) and fibrinogen in the blood are independent risk factors for cardiovascular disease.

In a study published in the journal Science on December 2, scientists from the University of Maryland and Regeneron Genetics Center found that a variant of the B4GALT1 gene is not only related to lower levels of low-density lipoprotein cholesterol, It is also related to a decrease in fibrinogen levels. This association seems to significantly reduce a person’s risk of heart disease.

Mice carrying this mutation also showed decreased levels of low-density lipoprotein cholesterol and fibrinogen, confirming the effect of this mutation. Researchers say this is the first time they have discovered a genetic variant that can significantly reduce the levels of two heart disease risk factors (people with this mutation have a 35% lower risk of heart disease).

This discovery may lead to new treatments to help prevent clogged arteries, blood clots and cardiovascular disease.

Milestone target ③: IL-27

  • Magazine:Nature
  • Field: Obesity
  • Paper: https://doi.org/10.1038/s41586-021-04127-5



On November 24, Nature published online research papers by Professor Yin Zhinan’s team from Jinan University.

This study found for the first time the protective effect of IL-27 signaling pathway in metabolic diseases, and for the first time proved that IL-27 receptor (IL-27Ra, or WSX-1) is expressed on non-immune cells-adipocytes And play an important function.

This discovery changes the existing understanding of the function of IL-27. As an immunomodulatory molecule, in addition to being mainly expressed on T cells and playing a role and function in infection immunity and autoimmune diseases, this work uncovered IL-27.

The -27 signaling pathway plays an important role in metabolic diseases and also provides a new target for the treatment of obesity-related metabolic syndrome in the future. ( Recommended reading: Nature’s latest achievement of Yin Zhinan’s team: A new target for immunotherapy for obesity-IL-27 )

Milestone target④ : CLIP1-LTK

  • Magazine:Nature
  • Field: Cancer (non-small cell lung cancer)
  • Paper: https://doi.org/10.1038/s41586-021-04135-5


On November 24, in a new study published in Nature, researchers from the National Cancer Center of Japan used the team’s self-developed lung cancer genome screening platform (LC-SCRUM-Asia) to screen for potential lung cancer carcinogens through a series of studies After verification, they found that CLIP1-LTK is a new target for the treatment of NSCLC.

After using the inhibitor lorlatinib to treat the first NSCLC patient with CLIP1-LTK, good clinical results were achieved. ( Recommended reading: Nature Milestone: New Target of Non-Small Cell Lung Cancer-CLIP1-LTK )

Milestone target ⑤: CRMP2, Ubc9

  • Magazine:Science Translational Medicine
  • Area : Pain
  • Paper: DOI: 10.1126/scitranslmed.abh1314



The voltage-gated sodium channel Nav1.7 is expressed on sensory neurons and plays a key role in pain. Therefore, it is an attractive target for pain treatment.

However, efforts to directly block this channel did not bring about Successful treatment. In a study published in the journal Science Translational Medicine on November 10, scientists from the University of Arizona reported that a small molecule targeting the Nav1.7 interacting protein, CRMP2, can indirectly regulate the activity of Nav1.7. And produced analgesic effects in animal pain models. CRMP2 (collapsin response mediator protein 2) is an accessory protein of Nav1.7.

Previous studies have shown that when lysine 374 is SUMOylated, CRMP2 promotes the expression of Nav1.7 on the plasma membrane, and when it restricts CRMP2-lys374 SUMOylation will increase the internalization of Nav1.7.

In this new study, scientists after extensive screening have found a compound that can target the pocket containing CRMP2-Lys374. In vivo studies have shown that the compound can block the interaction between CRMP2 and Ubc9 (the enzyme responsible for CRMP2-lys374 SUMOylation).

Nerve cell culture studies have shown that the compound eliminates the SUMOylation of CRMP2 and promotes clathrin-mediated internalization of Nav1.7.

Next, the researchers tested the compound’s effectiveness in various animal pain models through a series of administration routes.

They found that both intrathecal administration and oral administration showed analgesic effects. In addition, in the mouse model, this compound did not cause movement disorders or cause anxiety or depressive behavior, nor did it exhibit addictive side effects.

These findings indicate that selective targeting of CRMP2 SUMOylation may be a new way to exploit the therapeutic potential of Nav1.7.

Milestone target ⑥: DDR1

  • Magazine:Nature
  • Field: Cancer
  • Paper : https://doi.org/10.1038/s41586-021-04057-2



On November 3, in a study published in the journal Nature, scientists from George Washington University and other institutions discovered a key molecule called Discoid Domain Receptor 1 (DDR1), which actually prevents immune cells from approaching The “culprit” of tumors. Inhibiting the expression of DDR1 can reduce the immunosuppressive effect in TME, paving the way for tumor immunotherapy.

It is worth mentioning that on the same day that the paper was published, Parthenon Therapeutics, which obtained the patent authorization for the research, also announced the completion of a US$65 million Series A financing. Among the investors is the giant Pfizer. ( Recommended reading: Just on the Nature, it was favored by Pfizer and other capital! What is the difference between the new target of cancer immunotherapy, DDR1?)

Milestone target⑦: GABA A receptor

  • Magazine:Nature
  • Field : Cancer
  • Paper: https://doi.org/10.1038/s41586-021-04082-1



In a study published in Nature on November 3, a research team from the Yokohama Institute of Physics and Chemistry and Kyoto University found that B cells can release gamma-aminobutyric acid metabolites (GABA, a well-known neurotransmitter) Molecule), GABA promotes the differentiation of monocytes into anti-inflammatory macrophages to secrete interleukin-10 (IL-10), thereby inhibiting the anti-tumor CD8 T cell response.

This GABA secreted by B cells points out a new development direction for cancer immunotherapy. (Recommended reading: Nature: A new target for cancer immunotherapy-GABA )

Milestone target ⑧: COP1

  • Magazine:Cell
  • Field : Cancer (Triple Negative Breast Cancer)
  • Paper: https://doi.org/10.1016/j.cell.2021.09.006



In a study published in Cell on September 27, researchers from the Dana-Farber Cancer Institute found that the absence of E3 ubiquitin ligase Cop1 in cancer cells reduces the secretion and secretion of macrophage-related chemokines. Tumor macrophages infiltrate and can enhance tumor response to immune checkpoint inhibitor therapy.

Therefore, Cop1 is a potential target for improving the immunotherapy effect of triple-negative breast cancer. ( Recommended reading: Improve the efficacy of PD-1 antibody! Cell reveals a new target for triple-negative breast cancer-Cop1 )

Milestone target ⑨: LRP1

  • Magazine: Cell
  • Field: Rift Valley Fever
  • Paper: https://doi.org/10.1016/j.cell.2021.09.001



Rift Valley Fever Virus (RVFV) is a zoonotic pathogen with pandemic potential. The entry of RVFV into cells is mediated by viral glycoprotein (Gn), but the relevant host factors are still unclear.

On September 23, in a paper published in Cell, scientists from the University of Pittsburgh and the University of Washington identified low-density lipoprotein receptor-related protein 1 (mouseLrp1/human LRP1) and heat shock through genome-wide CRISPR screening.

Protein (Grp94) and receptor-associated protein (RAP) are the key host factors for RVFV infection. RVFV Gn binds directly to a specific Lrp1 cluster and is independent of glycosylation.

In different cell lines, the addition of exogenous murine RAP domain 3 (mRAPD3) and anti-Lrp1 antibody can neutralize RVFV infection.

Infecting mice with pathogenic RVFV, and then subjecting the mice to mRAPD3 treatment can protect the mice from disease and death.

In summary, these data support Lrp1 as a host entry factor for RVFV infection and define a new target to limit RVFV infection.


Milestone target ⑩: TNK1

  • Magazine:Nature Communications
  • Field: Cancer
  • Paper: https://doi.org/10.1038/s41467-021-25622-3



TNK1 is a non-receptor tyrosine kinase whose biological function is unclear. In a paper published in the journal Nature Communications on September 9, scientists from Brigham Young University identified the TNK1 dependency in human primary cancers.

In cell culture and mouse models, active TNK1 can induce lymphoid cells to proliferate independently of growth factors. Research has identified a TNK1 inhibitor (TP-5801) that can effectively inhibit tumor growth in vivo.

Milestone target⑪ : HULC

  • Magazine: Science
  • Field: Phenylketonuria
  • Paper: DOI: 10.1126/science.aba4991



The functional role of long-chain non-coding RNAs (lncRNAs) in genetic metabolic diseases including phenylketonuria (PKU) is unclear.

On August 6, in a paper published in the journal Science, scientists from the University of Texas MD Anderson Cancer Center found that two lncRNAs (one in mice and one in humans) can interact with benzene Alanine hydroxylase interacts and regulates its function. Treatment with modified RNAs that mimic the function of such lncRNAs improved the disease phenotype of the mouse model of phenylketonuria.

Specifically, studies have confirmed that mouse lncRNA pairs and human HULC are related to phenylalanine hydroxylase (PAH). Mice that knocked out the lncRNA pair showed symptoms very similar to human PKU.

In hepatocytes differentiated from human induced pluripotent stem cells, HULC loss leads to decreased PAH enzyme activity.

Mechanism studies have shown that HULC regulates the enzymatic activity of PAH by promoting the interaction of PAH substrates and PAH cofactors. In order to develop a therapeutic strategy to restore liver lncRNAs, the researchers designed a GalNAc-HULC mimic to treat Pair −/− and Pah R408W/R408W mice.

The results showed that the level of phenylalanine in the mouse model was reduced , And the treatment improved the tolerance of mice to phenylalanine.

Milestone target⑫ : GPR75

  • Magazine:Science
  • field:obesity
  • Paper: DOI: 10.1126/science.abf8683



On July 2, a research team from the Regeneron Genetics Center reported in Science that they discovered that mutations in the GPR75 gene can prevent obesity.

Regeneron’s drug developers are using the company’s VelocImmune technology to generate antibodies from humanized mice to find drugs that can mimic the protective properties of GPR75 mutants.

It is worth mentioning that less than a month after the publication of this paper (July 27), AstraZeneca announced a collaboration with Regeneron to jointly research, develop and commercialize small molecule therapies targeting GPR75. (Recommended reading: “Skin gene” found! Regeneration Science published an article revealing a new target for obesity-GPR75 )

Milestone target ⑬: RBM39

  • Magazine:Cell
  • field:cancer
  • Paper: https://doi.org/10.1016/j.cell.2021.05.038



Changes in RNA splicing in cancer cells may also lead to the production of new epitopes. In a paper published in the journal Cell on June 24, scientists from the Fred Hutchinson Cancer Research Center and Memorial Sloan Kettering Cancer Center confirmed that pharmacological regulation of splicing through specific drug classes can produce true neoantigens , And trigger anti-tumor immunity, enhance the efficacy of immune checkpoint blocking therapy.

Immune cells can well tolerate the degradation of the auxiliary splicing factor RBM39 and type I PRMT inhibition (RNA splicing factor is the protein with the highest degree of arginine methylation.

Therefore, by inhibiting the type I or type II protein arginine methylation Drugs using PRMT to block arginine dimethylation strongly interfere with splicing) .

Mechanism studies have shown that the effect of splicing regulation to inhibit tumor growth and enhance the efficacy of checkpoint blocking therapy depends on host T cells and tumor MHC class I peptide presentation.

These results indicate that splicing regulation is an untapped source of immunogenic peptides and provide a means to increase the response to checkpoint blockade.

Milestone target ⑭: CSE

  • Magazine:Science
  • Field: Bacterial infection
  • Paper: DOI: 10.1126/science.abd8377


In a study published in Science on June 11, scientists at the New York University School of Medicine discovered a natural defense mechanism that protects bacteria from the usual lethal doses of antibiotics. By screening existing drug libraries, the scientists identified 3 candidate drugs that can effectively weaken the defense of bacteria by inhibiting an enzyme called cystathionine gamma-lyase (CSE) system.

The research results support the strategy of using small molecule enhancers to enhance the susceptibility of bacteria to antibiotics. ( Recommended reading: Challenging the problem of antibiotic resistance! Science reports a new idea: Breaking the bacterial defense system, CSE inhibitors show their power )

Milestone target ⑮: ELANE

  • Magazine:Cell
  • Field: Cancer
  • Paper: https://doi.org/10.1016/j.cell.2021.04.016



On June 10th, scientists from the University of Chicago published a paper in the Cell magazine describing a striking new mechanism through which the body’s own immune system can protect the host cell without harming it.

Eliminate cancer cells. Specifically, studies have found that human neutrophils release catalytically active neutrophil elastase (ELANE) to kill many types of cancer cells without harming non-cancer cells.

ELANE can inhibit the growth of primary tumors and produce CD8+T cell-mediated distal effects to attack distant metastases. These findings increase the possibility of developing ELANE as a broad anti-cancer therapy. ( Recommended reading: Cell: New cancer immunotherapy, which only kills cancer cells but does not damage normal cells )

Milestone target⑯ : METTL3

  • Magazine:Nature
  • Field: Cancer (leukemia)
  • Paper: https://doi.org/10.1038/s41586-021-03536-w



On April 26, researchers from the University of Cambridge published a study in the journal Nature, reporting a new treatment for AML.

This method uses methyltransferase like protein (METTL)3 as the target, which plays a key role in the process of converting DNA into protein, and develops a small drug molecule STM2457.

Studies have shown that STM2457 can effectively destroy the proliferation and expansion of leukemia cells in the AML mouse model, and significantly extend the lifespan of mice. ( Recommended reading: Nature Milestone: New tumor target METL3, potential first-in-class leukemia new drug appears )

Milestone target ⑰: DNP H1

  • Magazine:Science
  • Field: Cancer (breast cancer, ovarian cancer)
  • Paper: DOI: 10.1126/science.abb4542



 On April 9th, a team of scientists from the Francis Crick Institute in the United Kingdom published a milestone in Science.

They found that blocking a protein called DNPH1 to interfere with nucleotide metabolism can increase tumors Sensitivity to PARP inhibitors.

Studies have shown that “DNPH1 inhibitor combined with PARP inhibitor” is expected to improve the treatment of some breast cancer patients. (Recommended reading: PARP inhibitor “new partner”-DNPH1 inhibitor | Science milestone )

Milestone target ⑱: CD161

  • Magazine:Cell
  • Field : Cancer (diffuse glioma)
  • Paper: https://doi.org/10.1016/j.cell.2021.01.022


In a paper published in Cell on February 15, scientists from Dana-Farber Cancer Institute, Massachusetts General Hospital, and Broad Institute discovered a potential new target for immunotherapy of malignant brain tumors -CD161, the target is a molecule that inhibits the anti-cancer activity of T cells, thus greatly hindering the efficacy of immunotherapy.

When analyzing samples from patients with diffuse glioma, the researchers found that T cells that infiltrated the tumor expressed CD161. The CLEC2D molecules on tumor cells and immunosuppressive myeloid cells in the brain activate the CD161 receptor.

Eventually, the activation of CD161 weakens the attack of T cells on tumor cells. ( Recommended reading: Cell Milestone: Treating brain tumors, PD-1 is not good, this target is interesting!)

Milestone target⑲: NSD3

  • Magazine: Nature
  • Field: Cancer
  • Paper: https://doi.org/10.1038/s41586-020-03170-y



 On February 3, a paper published in the journal Nature revealed the mechanism behind NSD3’s cancer-promoting function.

NSD3 is a lysine (H3K36) methyltransferase at position 36 of histone H3, which catalyzes the dimethylation of H3K36, that is, the addition of two methyl groups.

Professor Gozani and his collaborators found that in human tumors, NSD3 becomes dysregulated, either with an increase in copy number or a missense mutation to increase its catalytic activity.

In addition, studies have shown that H3K36 dimethylation levels are elevated in tumors with overactive NSD3.

Using genome analysis techniques, scientists have discovered that oncogenic NSD3 catalyzes the dimethylation of H3K36 in the protein coding region of oncogenes, leading to higher expression rates of these genes.

An important set of experiments has shown that an increase in the copy number of NSD3 (more common than missense mutations) causes lung cancer cells to become “addicted” to the catalytic function of NSD3, because the loss of NSD3 can reduce H3K36 dimethylation and reduce cancer driver genes.

Expression to hinder cell growth. These results indicate that NSD3-mediated catalysis is a possible drug target in these tumors. (Recommended reading: Two new breakthroughs in Nature’s anti-cancer: New epigenetic target-NSD3 )

(source:internet, reference only)

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