Lijun Sun, PhD
Associate Professor of Surgery, Harvard Medical School
Director, Center for Drug Discovery and Translational Research, BIDMC
Jea Eun Cheong, PhD
Finith Jernigan, PhD
Steffi Knoener, PhD
The Center for Drug Discovery and Translational Research, which I direct, provides a platform and expertise in medicinal chemistry to promote bench-to-bedside translation. My laboratory has studied the optimal integration of molecular simulations into the generation of bioactive molecules. In collaboration with investigators at Harvard Medical School, we have applied this research methodology for the discovery of novel inhibitors of the protein-protein interaction (PPI) between interleukin (IL)-18 and its receptor (collaborator: Dr. Leena Pradhan-Nabzdyk, BIDMC), the lipogenic enzyme ATP-citrate lyase (ACL) (collaborator: Dr. Vikas Sukhatme, BIDMC), the CDC-like kinase (CLK) in highly aggressive cancers (collaborator: Dr. Bruce Zetter, Boston Children’s Hospital), the cell cycle modulators as cytotoxic agents in drug resistant cancer cells (collaborator: Dr. Barbara Wegiel, BIDMC), the mast cell degranulation (collaborator: Dr. Aristidis Veves, BIDMC), the indoleamine/tryptophan dioxygenase (IDO/TDO), as well as the arylhydrocarbon receptor (AhR) (collaborator: Dr. Elliot Chaikof, BIDMC).
IL-18 plays a significant role in driving the inflammatory processes responsible for the development of intimal hyperplasia (IH). Via molecular simulation and in silico screening, we recently identified small molecule compounds that inhibit IL-18 signaling with low micromolar potency. Preliminary data suggest the small molecules elicit IL-18 antagonistic activity by inhibiting the PPI between IL-18 and its receptor. We are actively engaged in the characterization and improvement of the novel inhibitors.
Overly activated mast cells are implicated in the pathology of a number of diseases, including diabetic neuropathy and diabetic foot ulcer. Mast cell activation and the release of a spectrum of proinflammatory mediators are controlled by calcium channels. We have synthesized a new class of calcium channel blockers that effectively inhibit channel function and mast cell degranulation. We have demonstrated efficacy in mouse models of diabetic wound healing and diabetic peripheral neuropathy.
In the ACL project, we showed that ACL inhibitors reduced the population of the cancer stem-like cells (CSC) in a lung cancer cell line (A549) and an engineered breast cell line. The ACL inhibitors also inhibited the tumorigenesis in 3D in vitro tumorsphere assays. Research by others has recently showed a role of ACL in directing the polarization of the M2 phenotype macrophages that in the tumor microenvironment promote cancer immune escape. Our hypothesis is that inhibition of ACL might offer a unique approach to eradicate cancer cells by simultaneously reducing CSC and immune suppression in tumors. We are currently characterizing novel ATP-competitive ACL inhibitors that interrupt the rate-limiting step of the enzymatic reaction.
IDO and TDO are promising drug targets in immuno-oncology. Via in silico screen of compound library, we have identified IDO or TDO selective inhibitors that belong to different chemical scaffolds from all the reported inhibitors. The in vitro activity of the initial screening hits in biochemical assays is improved by conducting lead optimization studies.
CLKs are a class of kinases that regulate the alternative splicing of messenger RNA and are considered attractive drug targets for cancer as well as neurodegenerative disorders. We have discovered a class of benzimidazoles as highly selectively CLK inhibitors that inhibited cancer growth in vitro and in vivo. Structure-activity relationship study is currently one focus of our research.
We have successfully established a number of collaborative research programs that are supported by extramural funding provided by a federal agency or by other sources. Our research has started to bear fruit in a number of dimensions. In addition to the discovery and dissemination of new knowledge (including eight peer-reviewed publications), one major objective of our center is to promote technological and therapeutic innovations that address highly unmet patients needs. One of the technologies invented in our laboratory was licensed by a venture capital firm, which formed the cornerstone platform technology in a biotech startup focusing on the discovery and development of novel anticancer and anti-inflammatory therapies. Further, we are in active discussions for multiple funding or licensing opportunities to advance our innovations toward improving patient care. Thus far, we have filed four U.S. provisional patent applications, and have planned to submit multiple additional applications, based on the inventions from our center:
- Substance P, Mast Cell Degranulation Inhibitors and Peripheral Neuropathy. Application # 62/162,972
- Chalcone Compounds. Application # 62/245,725
- Compounds for treating proliferative diseases. Application # 62/261,240
- Mast-Cell Modulators and uses thereof. Application # 62/278,722
In addition to regularly presenting our research in national and international conferences, I was also an invited speaker/chair in a number of drug discovery conferences, including: 12th Annual Drug Discovery Chemistry in San Diego, CA, 2017, and 14th Annual Mastering Medicinal Chemistry Conference in Boston, MA, 2017 (Session Chair). We have published invited editorial and review article (Trends in Pharmacol Sci by Cell Press) in cancer immunotherapy. I also served as a reviewer for the journal Eur J Med Chem.
Teaching, Training, and Education
I have been committed to the training of next-generation scientists who are passionate about translational biomedical research. My laboratory has welcomed visiting scholars from medical centers and industrial research institutes to work side by side with research fellows. In addition, we also provided internship opportunities for high school graduates who would enter colleges for higher education in basic and biological science. On numerous occasions, I have provided technical expertise to research fellows from collaborators’ laboratories, guided their study designs, and made impactful influence in their scientific development and professional careers. I am inspired by the success of the talented fellows and motivated to transform the center to become a platform of excellence for training and biomedical innovation.
Selected Research Support
Development of Small Molecule Inhibitors of IL-18 to Prevent Intimal Hyperplasia; NIH, 2016-2018; Co-PI Lijun Sun, PhD (Contact PI: Leena Pradhan- Nabzdyk, PhD)
Targeting activated mast cells in diabetic foot ulcers; Joslin DRC F&P Award, 2015-2016; PI: Lijun Sun, PhD
Facile synthesis of glycosulfopeptides and related bioconjugates; NIH, 2015-2019; Co-Investigator: Lijun Sun, PhD (PI: Elliot Chaikof, MD, PhD)
PSGL-1 glycopeptide mimetic for treatment of metabolic syndrome; NIH, 2016-2020; Co-Investigator: Lijun Sun, PhD (PI: Elliot Chaikof, MD, PhD)
Wang Y, Hedblom A, Koerner SK, Li M, Jernigan FE, Wegiel B, Sun L. Novel synthetic chalcones induce apoptosis in the A549 non-small cell lung cancer cells harboring a KRAS mutation. Bioorg Med Chem Lett 2016;26(23):5703-5706.
Koerner SK, Hanai J, Bai S, Jernigan FE, Oki M, Komaba C, Shuto E, Sukhatme VP, Sun L. Design and synthesis of emodin derivatives as novel inhibitors of ATP-citrate lyase. Eur J Med Chem 2017;126:920-928.
Jernigan FE, Hanai J, Sukhatme VP, Sun L. Discovery of furan carboxylate derivatives as novel inhibitors of ATP-citrate lyase via virtual high-throughput screening. Bioorg Med Chem Lett 2017;27(4):929-935.
Jernigan FE, Sun L. In silico discovery and therapeutic potential of IDO1 and TDO2 inhibitors. Future Med Chem 2017;9(12):1309-1311.
Cheong JE, Zaffagni M, Chung, I, Xu Y, Wang Y, Jernigan FE, Zetter BR, Sun L. Synthesis and anticancer activity of novel water soluble benzimidazole carbamates. Eur J Med Chem 2017;in press (DOI: 10.1016/j.ejmech.2017.11.037).
Cheong JE, Sun L. Targeting IDO1/TDO2-KYN-AhR pathway for cancer immunotherapy - challenges and opportunities. Trends Pharmacol Sci 2017;in press (DOI: 10.1016/j.tips.2017.11.007).