Small molecules in targeted cancer therapy: advances, challenges, and future perspectives Targeted cancer therapy has become the mainstream approach for cancer treatment due to its higher efficacy and lower toxicity compared to traditional chemotherapy. Since the approval of the first tyrosine kinase inhibitor imatinib in 2001, numerous small-molecule targeted drugs have been developed for cancer treatment. As of December 2020, 89 small-molecule targeted drugs have been approved by the US FDA and the National Medical Products Administration (NMPA) of China. Despite significant progress, small-molecule targeted drugs still face challenges such as low response rates and drug resistance. This review summarizes the current state of small-molecule targeted drugs, their mechanisms of action, and future directions. Small-molecule targeted drugs are classified into two categories: small molecules and macromolecules. Small-molecule drugs have advantages in pharmacokinetic properties, cost, patient compliance, and storage and transportation. They are widely used in cancer treatment, with targets including kinases, epigenetic regulatory proteins, DNA damage repair enzymes, and proteasomes. However, small-molecule drugs still face challenges such as low response rates and drug resistance. Kinase inhibitors are a major class of small-molecule targeted drugs. They work by inhibiting the activity of protein kinases, which are enzymes that catalyze the transfer of phosphate groups from ATP to protein residues. Kinase inhibitors can be classified into different types based on their mechanism of action. Type-I inhibitors bind to the active conformation of the kinase, while type-II inhibitors bind to an inactive conformation. Type-I/II inhibitors can be further divided into A and B subtypes based on their binding characteristics. Type III and IV inhibitors are allosteric in nature, while type V inhibitors are bivalent molecules that span two distinct regions of the kinase domain. Type-I to V inhibitors are all reversible, while type VI inhibitors are irreversible. ALK inhibitors are a type of kinase inhibitor that target the ALK gene. ALK is a single transmembrane tyrosine kinase that plays a role in the development of the nervous system. ALK can activate multiple downstream signaling pathways and has been implicated in various cancers. ALK inhibitors such as crizotinib, ceritinib, alectinib, and brigatinib have been developed for the treatment of ALK-positive NSCLC. However, resistance to these inhibitors is a major challenge, with mutations such as L1196M and G1269A leading to relapse. Newer inhibitors such as lorlatinib have been developed to overcome resistance. c-Met inhibitors are another class of small-molecule targeted drugs that target the c-Met gene. c-Met is a receptor tyrosine kinase that plays a role in cell proliferation, survival, invasion, motility, scattering, angiogenesis, and epidermal-mesenchymal transitionSmall molecules in targeted cancer therapy: advances, challenges, and future perspectives Targeted cancer therapy has become the mainstream approach for cancer treatment due to its higher efficacy and lower toxicity compared to traditional chemotherapy. Since the approval of the first tyrosine kinase inhibitor imatinib in 2001, numerous small-molecule targeted drugs have been developed for cancer treatment. As of December 2020, 89 small-molecule targeted drugs have been approved by the US FDA and the National Medical Products Administration (NMPA) of China. Despite significant progress, small-molecule targeted drugs still face challenges such as low response rates and drug resistance. This review summarizes the current state of small-molecule targeted drugs, their mechanisms of action, and future directions. Small-molecule targeted drugs are classified into two categories: small molecules and macromolecules. Small-molecule drugs have advantages in pharmacokinetic properties, cost, patient compliance, and storage and transportation. They are widely used in cancer treatment, with targets including kinases, epigenetic regulatory proteins, DNA damage repair enzymes, and proteasomes. However, small-molecule drugs still face challenges such as low response rates and drug resistance. Kinase inhibitors are a major class of small-molecule targeted drugs. They work by inhibiting the activity of protein kinases, which are enzymes that catalyze the transfer of phosphate groups from ATP to protein residues. Kinase inhibitors can be classified into different types based on their mechanism of action. Type-I inhibitors bind to the active conformation of the kinase, while type-II inhibitors bind to an inactive conformation. Type-I/II inhibitors can be further divided into A and B subtypes based on their binding characteristics. Type III and IV inhibitors are allosteric in nature, while type V inhibitors are bivalent molecules that span two distinct regions of the kinase domain. Type-I to V inhibitors are all reversible, while type VI inhibitors are irreversible. ALK inhibitors are a type of kinase inhibitor that target the ALK gene. ALK is a single transmembrane tyrosine kinase that plays a role in the development of the nervous system. ALK can activate multiple downstream signaling pathways and has been implicated in various cancers. ALK inhibitors such as crizotinib, ceritinib, alectinib, and brigatinib have been developed for the treatment of ALK-positive NSCLC. However, resistance to these inhibitors is a major challenge, with mutations such as L1196M and G1269A leading to relapse. Newer inhibitors such as lorlatinib have been developed to overcome resistance. c-Met inhibitors are another class of small-molecule targeted drugs that target the c-Met gene. c-Met is a receptor tyrosine kinase that plays a role in cell proliferation, survival, invasion, motility, scattering, angiogenesis, and epidermal-mesenchymal transition