Novel modalities of recently approved drugs

Dr Sheraz Gul reviews the drug approvals from 2021 and highlights the novel modalities of molecules that target KRAS and HIF-2α, which have historically been considered as undruggable.

A group of medicine pills and antibiotics balancing on top of each other.

As multipronged approaches are increasingly being exploited to discover drugs, it is expected that the term ‘druggable’ will be applied more commonly for challenging drug targets.

The US Food and Drug Administration (FDA) approved 50 drugs in 2021, which is slightly under the 53 approvals seen in 2020. Of the 2021 approvals, 30 percent were oncology drugs and 52 percent for orphan diseases. As a consequence, many of the drugs underwent priority review as well as being associated with breakthrough designations. Although many of the approvals were for the well-known protein target classes, the approval of small molecule modulators of previously considered undruggable targets justifies increasing R&D investment in this area.

The mutated Kirsten rat sarcoma viral oncogene homologue (KRASG12C) in non-small cell lung cancer (NSCLC) has been a particularly challenging target as it has picomolar affinity for guanosine triphosphate (GTP) and lacks appropriate binding pockets. The breakthrough drug sotorasib covalently and irreversibly binds to a pocket that is present only in the inactive guanosine diphosphate (GDP)‑bound conformation, trapping KRASG12C in the inactive state and inhibiting KRAS oncogenic signalling. During clinical trials, tumour shrinkage and disease control were observed in the majority of patients with rapid and durable clinical benefit in patients with KRASG12C NSCLC.

Belzutifan is a first-in-class allosteric inhibitor of the hypoxia-inducible factor‑2α (HIF-2α) transcription factor and is the result of significant research exploring the link between von Hippel‑Lindau (VHL) disease and vascularised tumours. Targeting other transcription factors such as the NF‑κB master regulator for modulation of complex formation, degradation, translocation, DNA binding and activation is now a reality.

Two antibody drugs have been approved that target proprotein convertase subtilisin-like/kexin type 9 (PCSK9) by preventing its binding to the low-density lipoprotein receptor (LDLr). In contrast, MK-0616, a picomolar potent small molecule against PCSK9 that can be administered orally, is currently undergoing evaluation in a clinical trial for hypercholesterolemia ( Identifier: NCT05261126). This effort successfully demonstrates that mode of action studies on other targets such as protein-protein interactions accelerated by applying proteomics, cryo-electron microscopy (cryoEM), protac and computational techniques can lead to the identification of drugs with novel modalities.

About the author

Dr Sheraz Gul is the Head of Assay Development and Drug Repurposing at the Fraunhofer Institute, Germany. He has professional experience in the field of drug discovery, assay development and screening gained whilst employed in academia. He has co-authored more than 80 peer-reviewed papers, book chapters and patents including the Enzyme Assays: Essential Data handbook. He also has an interest in education and thus far has organised 46 drug discovery workshops since 2011 across the globe and trained 880 scientists.


  1. Skoulidis, et al. Sotorasib for lung cancers with KRAS p.G12C mutation. N. Engl. J. Med., 2021, 384:2371-2381. Doi: 10.1056/NEJMoa2103695.
  2. Jonasch, et al. Belzutifan for renal cell carcinoma in von Hippel-Lindau disease. N. Engl. J. Med., 2021, 385:2036-2046. Doi: 10.1056/NEJMoa2103425.
  3. Tucker, et al. A series of novel, highly potent, and orally bioavailable next-generation tricyclic peptide PCSK9 inhibitors. J. Med. Chem., 2021, 64:16770-16800. Doi: 10.1021/acs.jmedchem.1c01599.

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