Due to the advantages in efficacy and safety compared with traditional chemotherapy drugs, targeted therapeutic drugs have become mainstream cancer treatments. Since the first tyrosine kinase inhibitor imatinib was approved to enter the market by the US Food and Drug Administration (FDA) in 2001, an increasing number of small-molecule targeted drugs have been developed for the treatment of malignancies. By December 2020, 89 small-molecule targeted antitumor drugs have been approved by the US FDA and the National Medical Products Administration (NMPA) of China. Despite great progress, small-molecule targeted anti-cancer drugs still face many challenges, such as a low response rate and drug resistance. To better promote the development of targeted anti-cancer drugs, we conducted a comprehensive review of small-molecule targeted anti-cancer drugs according to the target classification. We present all the approved drugs as well as important drug candidates in clinical trials for each target, discuss the current challenges, and provide insights and perspectives for the research and development of anti-cancer drugs.

Insufficient brightness of fluorophores poses a major bottleneck for the advancement of super-resolution microscopes. Despite being widely used, many rhodamine dyes exhibit sub-optimal brightness due to the formation of twisted intra­molecular charge transfer (TICT) upon photoexcitation. Herein, we have developed a new class of quaternary piperazine-substituted rhodamines with outstanding quantum yields (Φ = 0.93) and superior brightness (ε × Φ = 8.1 × 104 L·mol–1·cm–1), by utilizing the electronic inductive effect to prevent TICT. We have also successfully deployed these rhodamines in the super-resolution imaging of the microtubules of fixed cells and of the cell membrane and lysosomes of live cells. Finally, we demonstrated that this strategy was generalizable to other families of fluorophores, resulting in substantially increased quantum yields.

No abstract

Rhodamine derivatives and analogues have been widely used for different super-resolution imaging techniques, including photoactivated localization microscopy (PALM). Among them, rhodamine spirolactams exhibit great superiority for PALM imaging due to a desirable bright–dark contrast during the photochromic switching process. Although considerable attention has been paid to the chemical modifications on rhodamine spirolactams, the on-time of photochromic switching, one of the key characteristics for PALM imaging, has never been optimized in previous developments. In this study, we proposed that simply installing a carboxyl group close to the lactam site could impose an intramolecular acidic environment, stabilize the photoactivated zwitterionic structure, and thus effectively increase the on-time. On the basis of this idea, we have synthesized a new rhodamine spirolactam, Rh-Gly, that demonstrated considerably longer on-time than the other tested analogues, as well as an enhancement of single-molecule brightness, an improvement on signal-to-noise ratio and an enlargement of total collected photons of a single molecule before photobleaching. Finally, super-resolution images of live cell mitochondria stained with Rh-Gly have been obtained with a good temporal resolution of 10 s, as well as a satisfactory localization precision of ∼25 nm. Through self-labeling protein tags, Rh-Gly modified with a HaloTag ligand enabled super-resolution imaging of histone H2B proteins in live HeLa cells; through immunostaining antibodies labeled with an isothiocyanate-substituted Rh-Gly, super-resolution imaging of microtubules was achieved in fixed cells. Therefore, our simple and effective strategy provides novel insight for developing further enhanced rhodamine spirolactams recommendable for PALM imaging.