asked: What exactly is targeted therapy for tumors?
Let us look back at the development of cancer drugs.
Modern medicine and physiology believe that the progression of tumors from sudden onset to subsequent evolution is mainly the result of genetic and clonal selection, and is a pathogenesis process involving multiple factors, multiple steps, and multiple genes. Its three significant basic characteristics are immortality, migration and loss of contact inhibition. Its specific manifestations are: ① evading immunity and growth inhibition; ② ignoring differentiation and signal instructions; ③ having the ability to proliferate indefinitely and evading apoptosis; ④ Invasiveness and ability of to induce angiogenesis.
Directly killing or removing cancer cells through some means is a very direct means of treating cancer . For example, traditional radiotherapy, chemotherapy, and surgical treatment are still important means of treating cancer, but these methods often have therapeutic effects. The shortcomings of incompleteness and excessive harm to the human body. In the past 20 years, a series of remarkable new developments have occurred in the research and development of anti-cancer drugs, which are based on people's deepening understanding of genes and epigenetics . When we discovered that gene and epigenetic mutations play an important role in regulating the biochemical reaction process of cells and the signaling pathway , we gained a deep understanding of the internal reasons why tumors produce the above characteristics, and also enabled us to target those involved. Important members of biochemical reactions and signaling pathways - endogenous small molecules, proteins (enzymes, receptors, etc.), and nucleic acids are specifically regulated to develop drugs, and targeted therapy emerged as the times require.
The 1950s
The birth of the first generation of anti-cancer drugs
The 1950s witnessed the birth of the first generation of anti-cancer drugs. Most of these drugs were cytotoxic molecules selected from a large number of compounds. They destroyed the DNA and inhibited the growth of tumor cells. DNA synthesis may interfere with the division of cells into , thereby inhibiting tumor growth. For example, the natural product microtubule inhibitor paclitaxel , the structurally modified cyclophosphamide and ifosfamide , etc.
The discovery of paclitaxel (Figure 1) takes us back to the 1960s, when the NCI, led by Dr. Jonathan Hartwel, tried to find new anti-cancer leads from natural sources, especially plant samples. You may be curious why NCI looks for new clues from nature. In fact, the answer is very simple. There are huge flora, fauna and microorganisms there, which provide humans with a treasure trove of natural products. NCI scientists discovered that paclitaxel extracted from the bark of the cedar tree has anti-cancer activity, and subsequently began structural identification and synthesis research on paclitaxel, and further explored the possibility of its anti-cancer use. In the early 1990s, after strict and standardized phase 1, phase 2, and phase 3 clinical trials, paclitaxel finally became a success and was officially used in clinical cancer treatment. Today, it has been widely used clinically for the treatment of breast cancer, ovarian cancer, some head and neck cancers, and lung cancer. Although paclitaxel plays an important role in the treatment of cancer, it, like other chemotherapy drugs, has a major flaw - the side effects are too great. For advanced patients, it can almost be said to kill the enemy by 800 and damage itself by 1,000. , so it cannot be regarded as a perfect anti-tumor drug.
Figure 1 Structural formula of taxane anticancer drugs
In the 21st century
kinase inhibitors kicked off the prelude to targeted tumor therapy
Entering the 21st century, the first small molecule BCR-ABL (a kinase) inhibitor ima Tinib (trade name: Gleevec) (Figure 2) is on the market for the treatment of late-stage Philadelphia chromosome -positive chronic myelogenous leukemia (CML), marking that tumor treatment has gradually entered the targeted era. Unlike paclitaxel, imatinib has a simpler structure and was synthesized from the beginning. Its discovery is the product of modern drug design. Its mechanism of action (MOA) is clear and it can specifically target the corresponding target.
Figure 2 The structural formula of imatinib
The discovery of imatinib greatly encouraged relevant researchers. People’s understanding of targeted treatments such as kinase inhibitors has also become deeper, and many new drugs have subsequently emerged. Kinase inhibitors. Sunitinib is a representative one.Sunitinib (Figure 3) is a type I kinase inhibitor that targets multiple receptor tyrosine kinases .
Figure 3 Structural formula of sunitinib
This drug was discovered by SUGEN when trying to discover an indolin-2-one that can inhibit two receptor tyrosine kinases (RTKs) at the same time. Unlike paclitaxel, sunitinib was obtained artificially from the beginning, and its synthesis route is shown in Figure 4.
Figure 4 Synthetic route of sunitinib
Structural biology research revealed the reason why sunitinib can inhibit the activity of kinase . After sunitinib binds to the ATP binding site of VEGFR2 (Figure 5a), it can The activation loop is forced to adopt the DFG-out conformation (Figure 5b), thereby inactivating the kinase and blocking cell signaling.
Figure 5 Sunitinib binds to the ATP binding site of VEGFR-2
(a) shows the amino acid responsible for ATP binding, (b) the effect of sunitinib binding on the conformation of the activation loop (PDB ID1: 4AGD) Sunitinib was approved for marketing in 2006 for the treatment of advanced renal cell carcinoma (RCC), gastrointestinal stromal tumor (GIST), and advanced pancreatic neuroendocrine tumors (pNET).
looks back at the development history of tumor drugs. The overall development trend of anti-cancer drugs is from classic chemotherapy drugs (such as paclitaxel) to targeted tumor drugs (such as kinase inhibitors). Targeted tumor drugs represent a milestone in the development of tumor drugs. The upgrade from radiotherapy and chemotherapy to precision treatment has opened a new era.
Anti-cancer therapy - from drug discovery to clinical application
"Anti-cancer therapy - from drug discovery to clinical application" is co-edited by Dr. Adam Todd and Dr. Jason H. Gill, School of Pharmacy, Newcastle University, UK, and Professor Paul W. Groundwater, School of Pharmacy, University of Sydney, Australia. The Chinese version of "Clinical Application" is officially available to everyone.
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This book comprehensively introduces the basic science and clinical applications of anti-cancer drugs. In the first part, it introduces cancer and treatment methods, covering the etiology, cellular and molecular basis of cancer; in the second part In the first part, the author mainly explains the discovery, synthesis, mode of action, resistance mechanism and adverse reactions of anti-cancer drugs; the third part focuses on certain specific cancers and elaborates on some anti-cancer drug singletons that appear in the second part. Practical clinical therapeutic applications with or in combination. This book is for researchers who are committed to cutting-edge cancer scientific research and clinical research to understand the etiology, cellular and molecular basis of cancer, and to be familiar with the discovery, mode of action, resistance mechanism of anti-cancer drugs, as well as real-world data on single or combined use. It is profoundly beneficial and will help promote the progress of preclinical and clinical anti-cancer therapies.
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