CORE SPOTLIGHT: Medicinal Chemistry Core
April 13, 2017
In this DF/HCC News Spotlight Edition, we present The DF/HCC Medicinal Chemistry Core which collaborates with researchers to advance their understanding of disease and accelerate the development of novel therapeutic agents. The Core can assist with all aspects of small molecule drug discovery, from the provision of suitable tool compounds to interrogate basic biology to the optimization of promising lead compounds for animal studies. The Core's labs are fully equipped for synthetic organic chemistry on a small to multi-gram scale, with access to the NMR facilities at DFCI and Harvard Medical School.
Summer 2016: The labs at Dana-Farber’s harbor campus were expanded and upgraded during the summer of 2016, doubling the capacity to 8 chemistry fumehoods.
- Medicinal chemistry consultation
- - Input for grant applications, project screening strategies, HTS analysis
- Identification and provision of tool compounds
- Long-term drug discovery collaborations
- - Optimization of hit compounds into advanced lead molecules with the potential for further development
Novel Targets for Waldenstroms Macroglobulinea
Steven Treon, MD, PhD (DFCI)
The Medicinal Chemistry Core is collaborating with Steven Treon, MD, PhD (DFCI) to identify novel targets and compounds for Waldenstrӧm’s macroglobulinemia (WM). WM is a type of non-Hodgkin’s lymphoma caused by an L265P mutation in myeloid differentiation primary response gene 88 (Myd88). Myd88 is a scaffolding protein that interacts with a subset of the TLR and IL receptors to activate NF-κB which promotes cancer cell proliferation. There are no known small molecule inhibitors of Myd88 thus Dr. Treon sought to block Myd88L265P signaling indirectly by inhibiting targets that propagate signal from Myd88L265P to NF-κB. Mutations in MYD88 promote Myddosome self-assembly to trigger NF-ĸB signaling in the absence of toll-like or interleukin 1 receptor signaling through IL-1 receptor kinases (IRAK1/4) or Bruton tyrosine kinase (BTK). Ibrutinib is a multi-targeted kinase inhibitor that covalently targets the Tec-family of tyrosine kinases including BTK and is highly active in previously treated WM patients, producing an overall response rate of 91%. However, many responses are partial, and persistent IRAK1/IRAK4 activity maintains NF-ĸB pro-survival signaling of malignant lymphoplasmacytic cells (LPCs) in WM patients on ibrutinib. Knockdown experiments showed the critical function of IRAK1 over IRAK4. Based on these findings we developed a potent and highly selective inhibitor of IRAK1 and showed that it synergized with ibrutinib to suppress growth of WM cell lines and tumor cells isolated from patients. Studies are ongoing to develop compounds suitable for study in animal models of WM. More recently, in collaboration with Dr. Treon, we discovered that mutations in MYD88 also promote HCK activation by interleukin 6 (IL-6). Through an industry sponsored research collaboration we have developed orally bioavailable HCK inhibitors that are well tolerated in animals and currently being investigated in murine models of MYD88 mutant WM and ABC-DLBCL.
Contribution of the Core:
- Compiled a biased collection of inhibitors that target enzymes known to signal downstream of Myd88
- Developed a potent and selective IRAK1 inhibitor that acted synergistically with ibrutinib in WM cell lines
- Validated HCK kinase as a novel target for WM and developed an orally bioavailable inhibitor suitable for animal models
- Yang G, Buhrlage SJ, Tan L, Liu X, Chen J, Xu L, Tsakmaklis N, Chen JG, Patterson CJ, Brown JR, Castillo JJ, Zhang W, Zhang X, Liu S, Cohen P, Hunter ZR, Gray N, Treon SP. HCK is a survival determinant transactivated by mutated MYD88, and a direct target of ibrutinib. Blood 2016; 127(25):3237-52 (PMID 27143257).
- Liu X, Hunter ZR, Xu L, Chen J, Chen JG, Tsakmaklis N, Patterson CJ, Castillo JJ, Buhrlage S, Gray N, Treon SP, Yang G. Targeting Myddosome Assembly in Waldenstrom Macroglobulinemia. Br J Hematol 2016; Apr 13. doi: 10.1111/bjh.14103 (PMID 27073043).
Inhibitors of Eya Phosphatase
Rosalind Segal, MD, PhD (DFCI)
The phosphatase Eya1 was recently identified by Rosalind Segal, MD, PhD (DFCI) as a potential drug target for medulloblastoma and pediatric astrocytoma. Possible tool compounds were identified from the literature. One of these, benzarone, showed dose-dependent effects in medulloblastoma and low-grade astrocytoma tumor cells, and an Eya1-specific gene expression cell assay. A biochemical Eya1 phosphatase assay is in development and approximately 50 additional analogs have been prepared by the Core to generate data to support a grant application. Preliminary cell data suggests that several compounds show enhanced potency over the initial lead molecule benzarone. Compounds have also been shared with researchers at BWH and BCH, exploring the role of the Eya phosphatases in high-grade astrocytomas and meningiomas. Pending the outcome of the grant application, the project may develop into a full drug discovery effort, with further optimization of the initial lead molecules for potency, selectivity and pharmacokinetic profile, targeting compounds able to cross the blood-brain barrier. As a consequence of a conserved and highly-charged catalytic site, phosphatase drug discovery has proven extremely challenging - inhibitors typically lack desirable drug-like properties and are not selective. Benzarone and the new analogs are believed to bind to an allosteric pocket, offering a better chance of delivering selective, orally available compounds than an active site phosphatase inhibitor.
Contribution of the Core:
- Identified possible tool compounds from the literature
- Provided input towards project strategy and grant application
- Prepared additional compounds, with some showing enhanced potency over the initial lead molecule
Inhibitors of MALT1
Ari Melnick, MD (Weill Cornell Medical Centre) and Hao Wu, PhD (BCH)
The Medicinal Chemistry Core has joined an ongoing collaboration between the groups of Ari Melnick, MD (Weill Cornell Medical Centre) and Hao Wu, PhD (BCH) to develop inhibitors of MALT1 for the treatment of the ABC-subtype of DLBCL. There was no path forward with the initially-reported small molecule MI-2, but alternative strategies towards identifying potential therapeutic agents have been developed. An HTS campaign failed to identify any additional lead series, with many of the hits determined to be aggregators under the assay conditions, or else too reactive and non-specific to be useful as starting points for further chemistry. Instead, the Core pursued a covalent substrate-based approach, based upon the VRPR tetrapeptide reported in the literature. Significant improvements were made to cell permeability, potency, and selectivity, and compounds have been identified with a PK profile suitable for animal studies. An initial patent application has recently been published, and aspects of the work will be presented at this year’s AACR meeting. Further approaches, including a series of allosteric inhibitors have also resulted in the filing of patent applications. This project is funded by R01 CA182736-02 (PI: Nathanael Gray, PhD (DFCI), Medicinal Chemistry Core Director).
Contribution of the Core:
- Developed alternative strategies to target MALT1 after initial hit compound proved non-optimizable, and HTS campaign failed to find other series
- Identified peptidomimetic compounds suitable for animal studies
- Filed three patent applications
Related Patent: WO 2017040304, Malt1 inhibitors and uses thereof
For more information or to contact the Medicinal Chemistry Core, visit the core website here.