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Aberrant formation of the NLRP3 inflammasome drives pyroptotic cell death in Myelodysplastic Syndrome Hematopoietic Stem and Progenitor Cells. The selective disruption of signal sensing and assembly of the NLRP3 inflammasome can offer targeted therapies to eliminate the MDS-initiating clones and remit chronic inflammation. Stapled-peptide inhibitors targeting the pyrin domain of the NLRP3 inflammasome were developed that can selectively disrupt NLRP3 inflammasome signal sensing and assembly. These inhibitors could be used to treat diseases in which inflammasome formation and the associated inflammation are critical determinants of the disease including MDS, Alzheimer’s, Parkinson’s, inflammatory bowel disease, gout, rheumatologic disorders, liver, kidney and cardiovascular diseases. Stapled peptide inhibitors have been synthesized with a KD as low as 68 nM, and a cell based IC50 as low as 1.5 μM.


  • MDS is a stem cell malignancy that largely afflicts individuals >60 years of age that is characterized by severe cytopenias. The annual incidence of MDS is 40-50,000 in the US according to Surveillance, Epidemiology and End Results (SEER) and Medicare records.
  • The most effective MDS and AML treatments also lead to many adverse systemic toxicities. Lenalidomide (Revlimid; Celgene) is currently the only MDS selective therapy on the market and it is only indicated for use in del(5q) MDS patients, which accounts for just 18% of all MDS patients. The market for this subset of MDS patients is still significant, with Revlimid generating $400M in 2013 revenue from MDS patients in the US alone. In contrast, these inflammasome inhibitors offer a strategy for targeted therapies for the majority of MDS patients.
  • The marketplace for NLRP3 is attractive. In April 2019, Novartis acquired IFM Tre for $310M which included three NLRP3 inhibitors portfolios, the most advanced of which went into the clinic just days before the deal was disclosed. In February 2019, Genentech acquired Jecure Therapeutics, for an undisclosed amount, to secure rights to its preclinical NLRP3 inhibitors. In addition, Inflazome, an inflammasome company developing small molecule drugs that block inflammation, completed a Series B financing round of $46 million to advance the Company’s first-in-class NLRP3 inflammasome inhibitors into clinical trials. The pyrin targeting stapled peptides represent a first in class therapeutic that has dual actions, inhibiting both Nlrp3 sensing of activating stimuli as well as inflammasome assembly. In MDS primary specimens the stapled peptides improved erythroid burst formation up to two-fold, and suppressed pyroptosis in vitro.


Stapled peptides containing a helix 2 sequence of a polypeptide pyrin domain were stabilized in solution by covalent linkages between amino acids. Such stapled pyrin peptides can inhibit pyrin domain interactions between NLRP3 and ASC polypeptides. Fmoc chemistry was used for peptide synthesis including a ring closing reaction before cleavage from the peptidyl resin. An FP saturation binding assay was used to determine the apparent binding affinity of the stapled peptides. The FP assays used 12.5 nM stapled peptide fluorescent tracer, 10 μM His6-NLRP3PYD or GSTASCPYD and different concentrations of the tested inhibitors in 25 μL of assay buffer. The data were analyzed by nonlinear least-square analyses using GraphPad Prism 5.0. A cell-based bioluminescent caspase-1 activity assay (Promega Caspase-Glo™ 1 Inflammasome Assay Kit G9951) was used to evaluate the inhibitory activity on inflammasome formation and caspase-1 activation in human THP-1 monocytes.


PCT International application filed on August 15, 2019 for Drs. Mark Ji and Alan List

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