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.
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.
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