Quantitative Chemical Biology

GPX4 is a selenoprotein that plays a critical role in protecting cells against oxidative stress and ferroptosis. The nucleophilic selenocysteine residue (Sec) located in the catalytic center of GPX4 can be exploited to design covalent inhibitors. Previously reported covalent GPX4 inhibitors always contain reactive alkyl chloride groups, conferring poor selectivities. Recently, the Schreiber group reported that ML210 , a direct covalent inhibitor targeting GPX4 in cells, exhibits much more potency and remarkable selectivity compared with chloroacetamide inhibitors. More interestingly, an unprecedented covalent binding mechanism is involved in the ML210 targeting GPX4 in cells. ML210 was previously reported as a ferroptosis inducer. Due to lack of an apparent covalent reactive group and inability to react with small molecule thiols directly, the covalent binding action of ML210 with its target proteins has never been disclosed. To identify that ML210 acts as a direct covalent ...

Abnormally activated Ca 2+ channels are related to many human diseases, including Stormorken Syndrome, which makes Ca 2+ release-activated Ca 2+ (CRAC) channel a very promising therapeutic target. Several small molecule therapeutics targeting CRAC channels have been developed, including the GSKs series and Synta 66 . Those compounds have relatively high specificity. Meanwhile, a controllable system that can be activated with a switch can probably serve as a convenient tool for further related research.    Photoswitchable chemistry has been applied to a lot of bioactive targets such as ion channels, receptors enzymes and nucleic acids. Recently, the Li group developed CRAC channel inhibitors that can be turned ‘on’ and ‘off’ by UV-light exposure. Scheme 1 . C onverting CRAC channel inhibitors, GSKs , into photoswitchable derivatives, piCRACs . Starting from the well-established GSK-based CRAC inhibitor ( Scheme 1 ), the authors developed a series of nitr...

Multiple myeloma (MM) is a malignancy of white blood cells called plasma cells that reside mainly in the bone marrow and is the second most common blood cancer. With increased understanding of biology, the current use of immunomodulatory (IM) drugs and proteasome inhibitors (PI) have taken over the therapeutic landscape for MM. The combination of bortezomib (PI) with lenalidomiede (IM) and dexamethasone is commonly the initial treatment of choice. Early intervention seems to provide a good outcome, but unfortunately, many patients eventually relapse. A major goal in MM treatment is to increase the efficacy of proteasome inhibitors and prevent relapse. To investigate this, Huang et al. used unbiased mass spectrometry-based phosphoproteomics to identify potential vulnerabilities after treatment with the PI carfilzomib and discovered that splicing related proteins had significant changes in phosphorylation that is undetectable upon examination of RNA and protein abundance. Treatment w...

In the past decade, targeted covalent inhibitors (TCIs) has experienced a resurgence due to its sustained target engagement and improved proteome-wide selectivity. Currently, targeting cysteine residues with acrylamides and other α, β-unsaturated carbonyl compounds is the predominant strategy in TCI development. Although lysine is more prevalent than cysteine and possesses lower mutation rates, lysine has been much less frequently considered and more challenging as a residue targeted by TCIs due to its low nucleophilicity. Recently, Jack Taunton and his colleagues reveled their two related work in JACS .   Based on the co-crystal structure of Hsp90 with a reversible inhibitor PU-H71, they designed two arylsulfonyl fluorides 1 and 2 and co-incubated them with Hsp90 protein (Figure 1a, b). Mass spectrometry detected the formation of a 1:1 covalent adduct. Mutation of Lys58 to arginine abrogated the covalent modification, indicating that the TCI selectively modified Lys58 (Fig...

(–)-Maximiscin ( 1 , Figure 1A) is a unique 4-hydroxy-2-pyridone alkaloid, a class of natural products historically represented by fascinating structural components and intriguing biological activities. Recently, 1 has been shown to induce DNA damage, activate DNA damage response pathways, and induce selective cytotoxicity against triple negative breast cancer (TNBC). The Baran group has reported the first total synthesis of 1 in a longest linear sequence of 10 steps. Their strategic bond disconnections are shown in Figure 1B. The synthesis is summarized in Scheme 1, and showcases a C–H methoxylation step that acts to desymmetrize the pseudosymmetric α-carbon of compound 10 (note that 8 is achiral and directing group 9 is enantiopure) to afford 11 . Notably, this is the most complicated example of this methodology, however there is a caveat to note, and it’s generally the “Achille’s Heel” of modern C–H activation methods, and that is the subsequent removal of the directin...

GlaxoSmithKline (GSK) previously reported a series of RIPK2 PROTACs with various E3 ligase binders (Figure 1). These PROTACs can degrade RIPK2 potently and efficiently in a concentration-dependent manner (Figure1). However, their poor solubility and high microsomal clearance limited their in vivo applications. To develop a RIPK2 degrader suitable for  in vivo  applications, the GSK group identified another IAP based RIPK2 PROTAC4 that is significantly different from PROTAC2, possessing a different RIPK2 binder, IAP ligase binder and linker (Figure2). PTROTAC4 can degrade RIPK2 in a time-dependent manner and shows reduced lipophilicity and lower clearance in hepatocytes. However, the modest binding affinity between the warhead of PROTAC4 and RIPK2 requires a high dose to reach efficient RIPK2 degradation. To address this limitation, the researchers performed extensive medicinal chemistry optimization based on PROTAC 4 and identified PROTAC 6 (Figure2), which contains an...

KRAS  is the most frequently mutated oncogene in human cancer. In the past few decades, the KRAS oncoprotein had always been deemed as an “undruggable target” due to lack of binding surface and tightly binding to its substrate GTP. In 2013, the Shokat group identified that the mutant cysteine KRAS G12C creates a new allosteric pocket “switch-II pocket” which can be exploited to design covalent inhibitors. KRAS G12C accounts for more than 50% of the incidences of KRAS mutations, involving in many cancers, such as non-small cell lung cancer (NSCLC), colorectal adenocarcinomas and pancreatic cancer. KARS G12C has been an attractive target for drug discovery and development in both academia and industry. MRTX849 is a potent, orally available covalent inhibitor of KRAS G12C developed by Mirati Therapeutics and currently undergoing Phase I/II clinical trials. Recently, a paper published in Journal of Medicinal Chemistry reported the design and optimization of MRTX849 ....

      The rapid spread of corona virus has lift up global concerns, especially with no effective treatment available so far. Different therapeutic approaches have been proposed, including developing vaccines and targeting protein machinery employed by virus RNA replication. Besides those effective yet conventional approaches, directly targeting RNA with small molecules can be a potential direction to develop antivirals.  RNA targeting with small molecules is an emerging field. Some recent work from academia, the Disney group in particular, and industry demonstrated that RNAs, just like proteins, can be selectively targeted by small molecules, which offers an alternative approach of finding effective drugs against COVID-19. Recently, a preprint on BioRvix from the Das group at Stanford University utilized computational prediction of different regions within SARS-CoV-2 RNA and offered a 3D structure dataset called ‘FARFAR2-SARS-CoV-2’. This dataset is proposed in this...

Resisting cell death, an original hallmark of cancer, is necessary for cancer growth. As a result, many therapeutic approaches have been made to induce cancer specific induction of cell death. This is especially important in pancreatic cancer, in which new targets are critically needed for this highly lethal cancer. There a multiple types of cancer cell death, for example, the caspase-dependent apoptosis, necroptosis, and pyroptosis and the lysosomal dependent autophagy. But today we are going to focus on the iron-dependent pathway ferroptosis.   Ferroptosis is characterized by iron dependency and lipid reactive oxygen species (ROS) accumulation. This pathway was first discovered in 2012 by the Stockwell group in which they observed that the small molecule erastin induced a non-apoptotic form of cell death in the N-ras mutated fibrosarcoma cell line HT-1080 and that they could recover cell death via inhibition using the novel ferroptosis inhibitor ferrostatin-1. Ferrosta...