Drug Discovery
Drug discovery is a complex and multidisciplinary process that aims to find and develop drug molecules that can effectively treat diseases. Drug discovery not only includes the exploration, design and development of new drugs, but also covers the entire process from laboratory to clinical application. This process usually spans multiple stages and involves in-depth collaboration in multiple fields such as chemistry, biology, pharmacology, and clinical medicine.
Drug Discovery
Drug discovery is a complex and multidisciplinary process that aims to find and develop drug molecules that can effectively treat diseases. Drug discovery not only includes the exploration, design and development of new drugs, but also covers the entire process from laboratory to clinical application. This process usually spans multiple stages and involves in-depth collaboration in multiple fields such as chemistry, biology, pharmacology, and clinical medicine.
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WRN
WRN (Werner syndrome helicase) is a member of the RecQ DNA helicase subfamily. RecQ helicases are involved in multiple DNA processing steps including DNA replication, double-strand break repair, transcription and telomere maintenance and are therefore considered to serve as ‘genome caretakers’. Studies have shown that WRN helicase is a synthetic lethal target for cancer cells with microsatellite instability (MSI), a form of genetic hypermutability that arises from impaired mismatch repair. MSI is associated with a high mutational load and occurs in more than 20 tumours types and is frequent in colon, ovarian, endometrial and gastric cancers. Depletion of WRN induces widespread DNA double-strand breaks in MSI cells, leading to cell cycle arrest and/or apoptosis. Thus, inhibiting the WRN helicase is an attractive strategy for the treatment of mismatch repair defective cancers.
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USP1
USP1 (Ubiquitin-Specific Protease 1) is a deubiquitinase enzyme that plays a key role in regulating protein stability and cellular processes by removing ubiquitin molecules from target proteins. It is involved in DNA damage repair, particularly through the regulation of the Fanconi anemia pathway, which is crucial for maintaining genomic stability. Overexpression of USP1 has been linked to cancer progression, as it can enhance DNA repair in tumor cells, contributing to resistance to chemotherapy. Targeting USP1 has gained attention as a potential therapeutic strategy to sensitize cancer cells to DNA-damaging agents and improve treatment outcomes.
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SOS1
SOS1 (Son of sevenless homolog 1) is a guanine nucleotide exchange factor (GEF) that mediates the exchange of GDP for GTP, thereby activating RAS proteins. SOS1 has two binding sites for RAS-family proteins; a catalytic site that binds GDP-bound RAS-family proteins to promote guanine nucleotide exchange and an allosteric site that binds GTP-bound RAS-family proteins which causes a further increase in the catalytic GEF function of SOS1. Stimulation of cells with growth factors leads to the association of SOS-Grb2 complexes with activated receptors and then to the stimulation of Ras through the juxtaposition of SOS and Ras at the membrane. Small molecule SOS1 inhibitors have been shown to be effective in downregulating active RAS in tumor cells with wild-type KRAS as well as tumor cells bearing a KRAS mutation. By preventing formation of the KRAS-SOS1 complex, the SOS1 inhibitors block reloading of KRAS with GTP, leading to antiproliferative activity.
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SHP2
Src homology-2-containing protein tyrosine phosphatase 2 (SHP2) is a member of a human protein phosphatases family (PTPs) and encoded by the PTPN11 proto-oncogene. Structurally, SHP2 consists of three domains－N-terminal and C-terminal SH2 recognition elements and a PTP catalytic domain. SHP2 modulates diverse cell signaling events that control metabolism, cell growth, differentiation, cell migration, transcription and oncogenic transformation. It interacts with diverse molecules in the cell, and regulates key signaling events including RAS/ERK, PI3K/AKT, JAK/STAT and PD-1 pathways downstream of several receptor tyrosine kinases (RTKs) upon stimulation by growth factors and cytokines. Mutations in the PTPN11 gene and subsequently in SHP2 have been identified in several human diseases, such as Noonan Syndrome, Leopard Syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, acute myeloid leukemia and cancers of the breast, lung and colon. SHP2, therefore, represents a highly attractive target for the development of novel therapies for the treatment of various diseases.
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PRMT5
Protein arginine methyltransferase 5 (PRMT5) is a major type II arginine methyltransferase that catalyzes the formation of symmetric dimethylarginine in a number of nuclear and cytoplasmic proteins. PRMT5 plays a critical role in regulating biological processes including transcription, cell cycle progression, RNA splicing, and DNA repair. Currently, an increasing number of studies have identified the roles of PRMT5 as a tumor-promoting factor in several cancers. PRMT5 promotes the carcinogenicity of various solid tumors including colon, breast, prostate, lung, liver, bone, ovarian, gastric, and pancreatic cancers with poor clinical outcomes. In recent years, novel inhibitors of the PRMT5/MTA complex have been developed for the treatment of MTAP-deleted cancers.
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Polθ
DNA polymerase theta (Polθ) is a unique, large (290 kDa) multifunctional A-family DNA polymerase that is required for DSB repair through the MMEJ pathway. Polθ plays a role in error-prone DNA repair pathways, including double-strand break repair and interstrand crosslink repair. The expression of Polθ is largely absent in normal cells but upregulated in breast, lung, and ovarian cancers. Inhibitors targeting Polθ have been developed to disrupt its enzymatic activity and impair DNA repair. These inhibitors have shown promise in increasing the sensitivity of cancer cells to DNA-damaging agents, improving treatment outcomes. Combining Polθ inhibitors with other DNA repair inhibitors or checkpoint inhibitors has also demonstrated synergistic effects. The study of Polθ as a therapeutic target and the development of its inhibitors represent a promising avenue for enhancing cancer treatment.
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PARP
Poly (ADP-ribose) polymerase (PARP) is a family of enzymes that play a key role in DNA repair by adding ADP-ribose units to proteins, a process essential for the repair of DNA damage. PARP1 and PARP2 are the most well-known members, involved in repairing single-strand breaks and maintaining genomic stability. Because of their role in DNA repair, PARPs have become attractive targets in cancer therapy, particularly in tumors with defects in other DNA repair mechanisms, such as BRCA1/2-mutated cancers. Inhibiting PARP can lead to synthetic lethality, selectively targeting cancer cells with impaired DNA repair.
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P53
P53 is a crucial tumor suppressor protein that plays a key role in regulating the cell cycle and maintaining genomic stability. It is often referred to as the "guardian of the genome" due to its ability to prevent the accumulation of mutations by inducing cell cycle arrest, DNA repair, or apoptosis in response to cellular stress or DNA damage. Mutations in the P53 gene are commonly found in various types of cancers, leading to uncontrolled cell division and tumor progression. As a therapeutic target, restoring P53 function has significant potential in cancer treatment strategies.
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KRAS
KRAS is a critical oncogene involved in various cancers, including lung, colorectal, and pancreatic cancers. It encodes a protein that controls key cell signaling pathways essential for cell growth and survival. Mutations in KRAS lead to its constant activation, driving tumor development. Targeting KRAS has been difficult due to the lack of clear binding sites. However, significant progress has been made in designing inhibitors that specifically target the mutated KRAS protein. Researchers are focusing on small molecules and other innovative approaches to block KRAS function, aiming to overcome resistance mechanisms and provide new therapeutic options for cancer patients.
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KIF18A
KIF18A is a kinesin motor protein that plays a critical role in the regulation of mitosis, specifically in the control of chromosome alignment during cell division. It functions by transporting microtubules to the mitotic spindle, ensuring accurate chromosome segregation. Overexpression or dysregulation of KIF18A has been implicated in various cancers, as it can contribute to chromosomal instability and tumor progression. Due to its pivotal role in cell division, KIF18A has emerged as a potential therapeutic target for cancer treatment, with inhibitors being explored for their ability to disrupt tumor cell proliferation.
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HPK1
The hematopoietic progenitor kinase 1 (HPK1), also known as MAP4K1, is a member of the mammalian Ste20-like family of serine/threonine kinases that operates via the JNK and ERK signalling pathways. HPK1 is a negative immune regulator of T cell receptor (TCR) and B cell signaling that is primarily expressed in hematopoietic cells. Studies using HPK1 kinase-dead knock-in mouse models have demonstrated that HPK1 kinase activity limits TCR signaling and cytokine production. In preclinical syngeneic models, loss of HPK1 kinase function was found to suppress tumor growth. These findings have validated HPK1 as a novel target for anti-cancer immunotherapy. Inhibition of HPK1 with small molecule inhibitors therefore has the potential to be a treatment for cancers and other disorders.
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EZH2
Enhancer of zeste homolog 2 (EZH2), as one of the most well-characterized epigenetic regulators, is the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) which functions to silence target genes by tri-methylating lysine 27 of histone H3 (H3K27me3). EZH2 plays a critical function in development and adult tissue homeostasis, and is closely associated with many diseases. Studies have found that EZH2 is highly expressed in a variety of solid tumors and hematological malignancies and is closely related to tumor proliferation, invasion, metastasis and poor prognosis. Therefore, EZH2 provides a pharmacological target for cancers.
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EGFR
Epidermal growth factor receptor (EGFR) is a transmembrane protein tyrosine kinase that functions as a receptor for members of the EGF family to trigger EGFR signal pathway in human epithelial cells, thereby regulating cell proliferation, invasion, metastasis, apoptosis, and angiogenesis. Overexpression and mutation of EGFR are closely related to the development of non-small cell lung cancer (NSCLC), and is also one of the important and valuable drug targets in NSCLC.
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CDK
Cyclin-dependent kinase (CDK) is a key regulator of the cell cycle, controlling progression through various phases by phosphorylating specific target proteins. CDK, in association with cyclins, drives processes such as DNA replication and mitosis, ensuring proper cell division. Dysregulation of CDK activity, often due to mutations in cyclins or other regulatory proteins, is a hallmark of many cancers, leading to uncontrolled cell proliferation. As a result, CDK has become an attractive target for cancer therapy, with CDK inhibitors being developed to halt tumor growth by disrupting cell cycle progression and inducing cell death in cancer cells.
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NLRP3
The NLR family pyrin domain containing protein 3 (NLRP3) inflammasome is a multimeric protein complex. Structurally, NLRP3 inflammasome contains three domains: the leucine-rich repeat-containing receptors (LRR) domain, the nucleotide-binding and oligomerization (NACHT) domain and pyrin domain (PYD). NLRP3 is a unique pattern recognition receptor (PRR) that can be widely stimulated by bacterial, viral and fungal pathogens, the environment and the host. Anomalous NLRP3 inflammasome activation has been implicated in the pathogenesis of a wide variety of human diseases and contributes to acute and chronic inflammation-associated complex diseases, including arthritis, atherosclerosis, diabetes, multiple sclerosis, Alzheimer’s disease and Parkinson’s disease. Accordingly, inhibitors of the NLRP3 inflammasome may be useful in the treatment of these diseases.
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JAK
JAK1 together with JAK2, JAK3, and TYK2 belong to the JAK (Janus-associated kinase) family of cytoplasmic tyrosine kinases that play important roles in cytokine and growth factor mediated signal transduction[1]. Dysregulated JAK activity leading to a constitutively activated signal transducers and activators of transcription (STAT) is strongly associated with immune-related diseases and cancers. Targeting JAK to interfere the signaling of JAK/STAT pathway has achieved quite success in the treatment of these diseases.
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IRAK4
Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) belongs to a family of four kinases (IRAK1, IRAK2, IRAK-M and IRAK4). IRAK4 is a serine/ threonine kinase which plays a crucial role in regulating Toll-Like receptors (TLR) and interleukin-1 receptors (IL-1R) signal. IRAK4 is recruited by the adaptor molecule Myeloid Differentiation primary response gene 88 (MyD88) after TLR activation, which results in activation of nuclear factor kappa B (NF-κB) and type I interferon (IFN) pathways. IRAK4 overactivation is linked with several autoimmune diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). In addition, IRAK4 has been shown to be associated with lymphocytic leukemia, lymphoma, and fibrotic disorders. Therefore, inhibitors of IRAK4 may be useful in the treatment of inflammatory disorders and cancers.
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IL-17A
IL-17A is a pro-inflammatory cytokine produced by T helper 17 (Th17) cells, playing a crucial role in immune responses, particularly in the defense against pathogens and in autoimmune diseases. It promotes the recruitment of neutrophils and the release of other cytokines, amplifying inflammation. Dysregulation of IL-17A signaling is associated with several chronic inflammatory conditions, such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease. Targeting IL-17A or its receptor has shown therapeutic potential in treating these diseases by reducing inflammation and preventing tissue damage, making it an attractive target for immune-modulatory therapies.