KRAS has been in the focus of cancer research for quite some time as it has been recognized as a key driver of tumor growth in several human cancers. In recent years, scientists could target inactive KRAS forms (like G12C). However, targeting the active-state mutations (such as G12R, Q61K, Q61L, Q61 variants) remained elusive, partially…
Optimization of PROTACs for in vivo applications is non-trivial, thought not impossible. A nice example on this topic represents freshly published paper in J. Med. Chem., showcasing successful optimization of a RIPK1 PROTAC degrader. Previous RIPK1 degrader LD4172 suffered from metabolic degradation and fast clearance (I highlighted the metabolic soft spots in the figure below)….
Although Hetero-Diels-Alder will play a central role, I am not going to speak about gender. Not today. Instead, I would like to highlight another major advancement in organic chemistry that enables synthesis of alkenes from alkynes. Alkynes serve as versatile building blocks in organic synthesis, drug discovery, and materials science. We chemists use them for…
About 85% of disease-related proteins lack suitable binding pockets for conventional drug discovery. While RNA-targeting approaches like siRNAs have shown promise (with several FDA approvals), they struggle with poor cellular uptake, limited tissue specificity, and complex, costly synthesis. Researchers from Peking University Shenzhen Graduate School introduce a novel modality for targeting “undruggable” proteins through RNA…
The field of PROTACs continues to evolve. A recent Nature Communications paper describes another self-assembling nano-PROTAC that co-degrades androgen receptor (AR) and HSP90 and shows promise for treatment of castration-resistant prostate cancer (CRPC). To save your precious time, here is my summary and highlights: Design and mechanismPsa-AR (nano-PROTAC) is a modular peptide comprising:– A PSMA-targeting…
Researchers often steer the design of CRBN-based PROTACs to achieve selective degradation of a single target while suppressing degradation of CRBN neo-substrates. Two different research groups published independently two publications where they approached this differently. By intentional design they developed dual degraders by combining the principles of PROTACs and molecular glue degraders. The first work…
How can bioorthogonal chemistry and mitochondrial targeting rewrite cancer immunotherapy? By creating enzyme-responsive nanoparticles that self-assemble in tumors and chemically “click” with an arsenic payload, scientists achieved complete tumor eradication and durable immune memory. Two main components – two small molecules (Fig. panel b)๐ ๐๐ซ๐จ๐๐ ๐-๐๐๐-๐๐๐:An ALP-responsive small molecule comprising a phosphate-caged fluorophore (mCy), a…
While biotech faces a funding downturn, radioligand therapy (RLT) is attracting major investments. The field stands at an important inflection point as next-generation alpha-emitting therapies prepare for phase 3 readouts in 2026. Why investors are betting on RLTsโ๏ธ Imaging-guided development enables visualization before treatmentโ๏ธ Physical, rather than pharmacological, cancer-killing mechanismโ๏ธ Unprecedented speed: candidate selection to…
Well, not quite yet. But maybe soon. Frontier Medicines evaluated E3 ligase DCAF2 (DTL/CDT2), as a novel ligase for targeted protein degradation by PROTACs (published in ๐๐ต๐ณ๐ถ๐ค๐ต๐ถ๐ณ๐ฆ): “๐๐ต๐ณ๐ถ๐ค๐ต๐ถ๐ณ๐ข๐ญ ๐ฃ๐ข๐ด๐ช๐ด ๐ง๐ฐ๐ณ ๐๐๐๐2 ๐ข๐ด ๐ข ๐ฏ๐ฐ๐ท๐ฆ๐ญ ๐3 ๐ญ๐ช๐จ๐ข๐ด๐ฆ ๐ง๐ฐ๐ณ ๐๐๐๐๐๐-๐ฎ๐ฆ๐ฅ๐ช๐ข๐ต๐ฆ๐ฅ ๐ต๐ข๐ณ๐จ๐ฆ๐ต๐ฆ๐ฅ ๐ฑ๐ณ๐ฐ๐ต๐ฆ๐ช๐ฏ ๐ฅ๐ฆ๐จ๐ณ๐ข๐ฅ๐ข๐ต๐ช๐ฐ๐ฏ” Why it is importantโ This work addresses a key limitation in PROTAC development: the…
It doesn’t happen very often to see a direct comparison of a molecular glue degrader and PROTAC, as it has been just published in J Med Chem: “๐๐ช๐ด๐ค๐ฐ๐ท๐ฆ๐ณ๐บ ๐ฐ๐ง ๐ข ๐๐ฆ๐ญ๐ฆ๐ค๐ต๐ช๐ท๐ฆ ๐ข๐ฏ๐ฅ ๐๐ฐ๐ต๐ฆ๐ฏ๐ต ๐๐๐6 ๐๐๐๐๐๐ ๐ธ๐ช๐ต๐ฉ ๐๐ง๐ง๐ช๐ค๐ข๐ค๐ช๐ฐ๐ถ๐ด ๐๐ฏ๐ต๐ช๐ฑ๐ณ๐ฐ๐ญ๐ช๐ง๐ฆ๐ณ๐ข๐ต๐ช๐ท๐ฆ ๐๐ค๐ต๐ช๐ท๐ช๐ต๐บ ๐ง๐ฐ๐ณ ๐ต๐ฉ๐ฆ ๐๐ณ๐ฆ๐ข๐ต๐ฎ๐ฆ๐ฏ๐ต ๐ฐ๐ง ๐๐ช๐ง๐ง๐ถ๐ด๐ฆ ๐๐ข๐ณ๐จ๐ฆ ๐โ๐๐ฆ๐ญ๐ญ ๐๐บ๐ฎ๐ฑ๐ฉ๐ฐ๐ฎ๐ข” Why it is interestingโ๏ธ Glue degraders as well…