This post briefly introduces chimeric molecules and companies working on them, contains a list of 10 recent “hot” papers in this field, and some predictions for where chimeras might head.

It’s Chinese New Year time, which means a significant part of the global biopharma supply chain has ground to a halt, due to our colleagues and suppliers in China taking much needed time off to reconnect with their families.  It’s also the Year of the “Rat,” which feels like an apt spirit animal for 2020 given the sad way the year has started.  I suggest we celebrate the “Chimera” this year instead, with the recent fireworks of new research articles on chimeric molecules.

Chimeric molecules are artificial molecules composed of at least two distinct molecular moieties that have separate functional activities.  The most successful chimeric drugs so far have been in the biologics universe (think fusion proteins like etanercept or chimeric antigen receptors on CAR-Ts), but in recent years, enthusiasm has exploded for novel small molecule chimeras to access previously “undruggable” space.

Chimeras for Small Molecule Drug Discovery

The most well-known chimeras involving small molecules are PROTACs, or proteolysis-targeting-chimeras.  These commonly have one molecular component which binds a target protein, and a second component which binds a protein involved in endogenous protein degradation such as cereblon or VHL.  By bringing the target protein into contact with protein degradation machinery, these chimeric molecules catalyze the degradation of the target protein using cells’ natural machinery.  Because this approach doesn’t depend on influencing enzymatic activity at a binding site, many new classes of intracellular targets can be modulated.

There’s still a gap between demonstrating in vitro activity with chimeras and turning them into oral pills. Several recently started companies have platforms focused on developing chimeric small molecules for clinical use. These include Arvinas, Kymera Therapeutics, C4 Therapeutics, Cullgen, and Nurix.  There’s also growing large pharma interest in this area as well – as Arvinas states in its 2018 Annual Report, by the end of 2018 Amgen, AZ, Celgene, GSK, Genentech, and Novartis all had disclosed preclinical investments in the field.

10 Recent Advances on Chimeras Involving Small Molecules

With new science around chimeric molecules continuing to expand and with a constant stream of new research introducing new ways to apply them, there’s no doubt investment in this space will continue to grow. In case you missed them, here’s a quick rundown of 10 of the most drug discovery relevant articles on chimeras that have appeared just in the last few months:

  1. RNA-Degrading Ribonuclease Targeting Chimeras (RIBOTACs) – Matt Disney’s lab at Scripps Florida recently disclosed a “RIBOTAC,” or ribonuclease targeting chimera, in PNAS.  The construct consists of a molecular element which binds to 3D folds in a target pre-miRNA, pre-miR21, and a ribonuclease-binding element, which recruits RNase L to degrade pre-miR21.   The construct is significantly more active in reducing target miRNA levels, and demonstrated in vivo activity in a mouse metastasis model. The authors believe the concept will be generalizable to targeting other structured RNAs.
  2. Protein Phosphatase Recruiting Chimeras (PhoRCs) – A team of Genentech and Pharmaron scientists led by Sayumi Yamazoe and Steve Staben recently demonstrated proof of concept for protein phosphatase recruiting chimeras, or “PhoRCs,” in J. Med. Chem.  The chimeras consist of target-binding elements linked to PP1 activators, which recruit the phosphatase PP1 to de-phosphorylate the protein of interest.  The chimera-induced de-phosphorylation of target proteins can drive a broad range of biological activities instead of leading to the degradation of a protein of interest.
  3. Reversible Covalent PROTACs for BTK Degradation – The London lab at the Weizmann Institute of Science in Israel recently posted work on reversible covalent PROTACs on ChemRxiv.  Covalent PROTACs have previously been explored, but the limitation there is irreversible binding negated the catalytic activity of PROTACs.  The authors demonstrate that BTK can be degraded with reversible covalent PROTACs based on a cyanoacrylamide reversible covalent warheads for BTK and a CRBN-binding element.  Reversibility was demonstrated through competition experiments with Ibrutinib.
  4. Antibody-Chimeric Degrader Conjugates – Genentech and WuXi scientists led by Tom Pillow and Pete Dragovich reported proof of concept for an antibody-chimera conjugate, in ChemMedChem.  A highly active chimeric BET degrader (GNE-987) containing a potent BET binder, a VHL-binding fragment, and a 10-methylene spacer was disclosed.  This molecule possessed poor DMPK properties, but conjugation of the molecule to a CLL1-targeting antibody through a novel disulfide-based carbonate linker resulted in a conjugate with favorable in vivo stability and antigen-dependent activity.
  5. Selective BCL-XL Degraders Based on Cancer Cell Specific E3 Ligase Expression – Guangrong Zheng and Daohong Zhou’s labs at U of F described a selective BCL-XL degrader, DT2216, in Nature Medicine.  BCL-XL inhibitors have been pursued extensively as anti-cancer agents due to their ability to promote apoptosis in certain cancers.  The challenge with previous BCL-XL inhibitors was activity in healthy hematopoietic cells, leading to on-target and dose-limiting thrombocytopenia.  DT2216, a chimera of AbbVie BCL-XL inhibitor ABT263 and a VHL E3 ligase binder, induces degradation of BCL-XL and demonstrates in vivo activity against several xenografts without thrombocytopenia since VHL is minimally expressed in platelets.
  6. Lysosome Targeting Chimeras (LYTACs) for Extracellular Targets – Carolyn Bertozzi’s lab at Stanford described lysosome targeting chimeras (LYTACs) consisting of antibodies fused to agonist glycopeptide ligands for the lysosome-targeting cell surface receptor, CI-M6PR, in a pre-print on ChemRxiv.  The LYTAC constructs allow extracellular proteins to be degraded through recognition by the antibody fragment and internalization to lysosomes by the CI-M6PR receptor agonist motif.
  7. Allosteric-Binding, Non-Ubiquitin-Dependent Chimeric Degraders of PCSK9 – Scientists at Merck, Kenilworth led by Whitney Petrilli, Gregory Adam, and Roman Erdmann recently disclosed a campaign to identify targeted degraders of PCSK9 in Cell Chem. Biol.  They were able to identify a single allosteric binder (~120 uM) to PCSK9 through an affinity selection/mass spec (AS/MS) of 200k compounds.  An improved binder (Ki = 59 nM) was identified through proximity-driven click chemistry, and binding in cell lysates was demonstrated through a CETSA assay.  A lead bifunctional molecule with a Arg(Boc)3 ubiquitin-independent proteasome-recruiting element was identified which achieved 60% reduction of PCSK9 levels at 20 uM.
  8. Autophagy-Targeting Chimeras (AUTACs) – The Arimoto lab at Tohoku University in Japan recently described autophagy-targeting chimeras (AUTACs) in Mol. Cell. These molecules contain guanine-based degradation tags which induce autophagy of their targeted proteins and fragmented mitochondria.  Proof of concept was shown by degrading MetAP2 and FKBP12 with AUTACs.  Nuclear proteins such as Brd4, however, are only accessible during mitosis, so AUTAC-based of this target was not as effective.
  9. Attempts to Degrade KRASG12C with Chimeras – The Gray, Fischer, and Westover labs of Harvard and UT Southwestern recently disclosed an attempt to create a CRBN-based KRASG12C degrader in Cell Chem. Biol. The chimeric degrader was able to degrade GFP-KRASG12C in reporter cells in a CRBN-dependent manner, but failed to degrade endogenous KRASG12C due to the inability of the degrader to poly-ubiquitinate endogenous KRASG12C.  They hypothesize that either the ubiquitinated lysine of GFP-KRASG12C was located on the tag, or that the membrane-localization of wild-type KRAS and the cytosolic/nuclear localization of CRBN is to blame.
  10. A Recent PROTAC Primer – Finally, if none of the above topics make any sense to you, George Burslem and Craig Crews of Yale have a nice primer on PROTAC development and use in Cell. The authors discuss case studies of effective PROTAC use, but also include a helpful discussion of disadvantages to PROTACs, including the long lead time for development, off-target effects, the unproductive “hook effect” at higher concentrations, and limited protein scope.

If you think I’ve missed something more important, please get in touch!

Some Predictions for Chimeras in 2020

In the spirit of sharing “fortunes,” I’ll leave you with some personal speculations about chimeric small molecules in 2020:

  • At least 3 new biotech companies will raise >25M each in 2020 to pursue the discovery/development of chimeric small molecules
  • A large pharma player will sign a big deal (>$500M biobucks) with another company with a focus on chimeric small molecules.  My personal speculation is it’ll involve GSK, Lilly, Sanofi, AZ, or AbbVie, in that order based on their desires to grow in oncology through business development.
  • Two new chimeric small molecule protein degraders enter the clinic in 2020, but no other chimeric small molecule modality does this year.

We’ll see how I did next year.  Let me know if you’ve got any of your own guesses! Happy Chinese New Year to all, and happy hunting!

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