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Lead Wistar Inventor
Emmanuel Skordalakes, Ph.D.

Unmet Need

Since 1991, advances in cancer therapies have correlated with a 22 percent drop in cancer deaths. In spite of these therapeutic advances, approximately one third of all cancer diagnoses in the United States are terminal (approximately 590,000 individuals in 2015) (1). Targeted immunotherapies show great promise for a fraction of these patients; however, available and proposed immunotherapies remain vulnerable to a multitude of cancer resistance mechanisms. In addition, many are biologicals or require modification of the patient’s cells in vitro – methods that pose practical hurdles that are both expensive and time-consuming.


Cancerous cells, unlike most healthy cells, “infinitely” proliferate largely due to upregulation of telomerase, a ribonucleoprotein complex that is essential for maintaining telomeric integrity following cell division. In fact, approximately85 percent of cancers require the activity of telomerase for cell proliferation, whereas telomerase activity is absent in non-germline, healthy, adult tissue (2). Therefore, selectively disrupting the function of telomerase would be an effective and safe means to significantly halt cancer progression (3). Currently, a limited number of groups are pursuing therapeutic applications for telomerase inhibitors; most notably, the Geron Corporation is employing proprietary inhibitory oligonucleotides (4). However, therapeutic success has been hampered by many factors, most notably the lack of complete abrogation of telomerase activity thus taking several months to observe signs of efficacy. Such a long therapeutic regiment is impractical for treating cancer. Clearly identifying highly effective and specific telomerase inhibitors is essential.

Stage of Development

Dr. Skordalakes generated a high-resolution structure of TERT, the full-length catalytic subunit of telomerase, co-crystalized with an RNADNA hairpin that mimics the RNA template and complementary telomeric DNA substrate (5).  Inclusion of the RNADNA hairpin provided unprecedented insights into the understanding of the structure, activity relationship of TERT. Leveraging this novel 3-D structure, the Skordalakes group identified novel target sites essential for telomerase ribonucleoprotein assembly and activity.

Computer-based docking of compounds into the crystal structure of the macromolecule (in silico screening) was used to filter large compound libraries and identified 125 theoretical ‘hits.’ In silico hits were validated using a biological assay of telomerase activity. This secondary screen identified four molecules with IC50 in the nanomolar, and a dozen with IC50 in the micromolar range (unpublished). Crystal structures of TERT in complex with these molecules identified their specific binding sites and mechanisms of action against telomerase.

Each of these high-affinity inhibitors was highly toxic against human cancers (e.g. breast, pancreatic, prostate, and skin) that are dependent on telomerase activity. Whereas, these high-affinity inhibitors had no effect on cultured fibroblasts and models of cancer that do not depend on telomerase activity, e.g. bone osteosarcoma. Moreover, the cancers vulnerable to the high-affinity inhibitors displayed telomere erosion and genomic instability, quintessential evidence of toxic telomerase inactivation. For each of these high-affinity inhibitors, the Skordalakes group has since determined the specific TERT binding site and mechanism of action.

Hit to Lead Series Development:

Forty-seven structural analogs of the top hit were identified and screened in biological assays for their effects on telomerase activity. This screen identified high-affinity compounds with quick therapeutic efficacy – on the order of one-to-two weeks in vitro (unpublished data).

Development Stage:

The lead series compounds have been tested in multiple in vitro models. Current efforts are focused on lead compound optimization and preclinical validation.

Intellectual Property

Wistar has developed a robust patent portfolio around the Skordalakes discovery program. US8,234,080, US8,377,992, US8,374,838, US8,518,940, and US9,234,230 and pending applications in process.

Collaboration Opportunity

We are actively seeking a collaborator to facilitate the final stages of lead optimization and characterization, generation of an IND package, and initiation of clinical trials. We also view this technology platform as a good start-up opportunity.


  2. Kim et al. Science. 1994 Dec 23;266(5193):2011-5. PMID: 7605428
  3. Neidle et al. Nat Rev Drug Discov. 2002 1(5):383-393. PMID: 12120414
  5. Bryan et al. Structure. 2015 6;23(10):1934-1942. PMID: 26365799
  6. Gillis et al. Nature. 2008 455:633-637. PMID: 18758444
  7. Rouda et al. Structure. 2007 15(11):1403-1412. PMID: 17997966