Key Projects

1. Maximizing Selectivity with Inhibitor Combinations

Ian R Outhwaite; Sukrit Singh; Benedict-Tilman Berger; Stefan Knapp; John D Chodera; Markus A Seeliger

Although drug combinations are a mainstay of modern oncology, toxicity remains a major challenge to introducing new combinations therapies. We explore the idea of using combinations of different compounds that all share a common target, but have different off-target effects. By developing a method to precisely adjust how much of each compound we want to use, we can reduce the off-targets effects of any single compound.

Key finding: we can greatly improve selectivity for therapeutic co-targets using inhibitor combinations

Paper here. Is target selectivity a challenge for your system of interest? Get in Contact

2. Targeting MET in human cancers

Ian R Outhwaite; Markus A Seeliger (and others)

Mutations in mesenchymal epithelial transition factor (c-MET/MET) protein kinase drives many human cancers. Additionally, MET signaling can act as a backdoor that helps tumors overcome drugs targeting other common oncogenes. In this ongoing work we are defining which drugs to use to target specific MET mutations, either as solo targets or in combination with other common targets in human cancers.

If you would like to learn more, view the RePORTER page

Publications

^* co-equal contribution
^# co-corresponding

(2024)

Leyte-Vidal A, DeFilippis R, Outhwaite IR, Kwan I, Lee JY, Leavitt C, Miller KB, Rea D, Rangwala AM, Lou K, Patel S, Alvarez A, Shokat KM, Bahar I, Seeliger MA, Shah NP. Absence of ABL1 exon 2-encoded SH3 residues in BCR::ABL1 destabilizes the autoinhibited kinase conformation and confers resistance to asciminib. Accepted at Leukemia. https://doi.org/10.1038/s41375-024-02353-0

Jennings RB^*, Outhwaite IR^*, Granek IA, Haq F. The effects of the physical and professional workplace environments on the well-being of nursing staff. Accepted at The American Journal of Nursing, in publication.

Radin DP, Shifman S, Outhwaite IR, Sharma A, Bases R, Seeliger MA, Tsirka SE. Lucanthone, a Potential PPT1 Inhibitor, Perturbs Stemness, Reduces Tumor Microtube Formation, and Slows the Growth of Temozolomide-Resistant Gliomas In Vivo. JPET. https://doi.org/10.1124/jpet.123.002021

(2023)

Outhwaite IR, Singh S, Berger B.-T., Knapp S, Chodera JD, Seeliger MA. Death by a thousand cuts through kinase inhibitor combinations that maximize selectivity and enable rational multitargeting. eLife. doi: https://doi.org/10.7554/eLife.86189

Outhwaite IR, Seeliger MA. Kinase Activity: Probing conformational dynamics to understand kinase inhibition. eLife. doi: https://doi.org/10.7554/eLife.92753 [insight article]

Mingione VR^*, Paung Y^*, Outhwaite IR^*#, Seeliger MA^#. Allosteric regulation and inhibition of protein kinases. Biochem Soc Trans. doi: https://doi.org/10.1042/BST20220940 [review]

(2022)

Peterson AA^*, Rangwala AM^*, Thakur MK, Ward PS, Hung C, Outhwaite IR, Chan AI, Usanov DL, Mootha VK, Seeliger MA, Liu DR. Discovery and molecular basis of subtype-selective cyclophilin inhibitors. Nat Chem Biol. https://doi.org/10.1038/s41589-022-01116-1

Phillips HE, Jennings RB, Outhwaite IR et al. Motivation to Impact: Medical Student Volunteerism in the COVID 19 Pandemic. Med Sci Educ. doi: https://doi.org/10.1007/s40670-022-01639-1

(2020)

Hou X^*, Outhwaite IR^*, Pedi L, Long SB. Cryo-EM structure of the calcium release-activated calcium channel Orai in an open conformation. eLife. doi: https://doi.org/10.7554/eLife.62772