Study suggests LMTK3 inhibitors effective for breast cancer

Five year study suggests LMTK3 inhibitors could be effective for breast cancer treatment

November16th,2020
Mel J. Yeates

FALMER, U.K.—An international study, led by scientists at the University of Sussex, has provided evidence for an effective new target for breast cancer treatment. An article, entitled “The structure-function relationship of oncogenic LMTK3,” has been published in Science Advances.

The five year study suggests that LMTK3 inhibitors could be effectively used for the treatment of breast cancer, and potentially for other types of cancer as well. The structure of oncogenic LMTK3 (lemur tyrosine kinase 3) determines its role and functions, allowing drug inhibition as a new therapeutic strategy.

“By solving the crystal structure of LMTK3, we have demonstrated that it possesses all of the hallmarks of an active protein kinase,” noted Georgios Giamas, professor of Cancer Cell Signalling at the University of Sussex, who led the research. “LMTK3 plays a pivotal role in controlling cellular processes, and we have previously shown that active LMTK3 makes some cancer treatments (e.g., chemotherapy and endocrine therapies) less effective.”

“LMTK3 … has all the hallmarks (key features and residues) of an active protein kinase, able to be activated, to bind and hydrolyze ATP (Fig. 1 and figs. S1 and S2),” explains the article. “In particular, the K/E/D/D signature motif plays important structural and catalytic roles and comprises residues Lys193 in the β3 strand, Glu210 in the center of the αC helix, Asp295 of the catalytic loop, and Asp313, the first residue of the activation segment.” 

“We are now in the process of taking this research to the next stage by developing LMTK3-specific drugs. We hope that in the next five years we will be undertaking clinical trials, which is incredibly quick for this type of process,” Giamas continued.

The development of oral LMTK3 inhibitors could have the potential for broad clinical utility, either as monotherapy or combination therapy. An LMTK3 inhibitor could be used alongside complementary therapies to increase the therapeutic efficacy, and to help overcome resistance to existing cancer therapies.

“It is often difficult to obtain large well diffracting crystals and LMTK3 was no exception,” added Robin Owen, principal beamline scientist of MX beamline I24 at Diamond Light Source. “Through close collaboration between the OPPF and I24 and exploiting the microfocused X-ray beam at I24 to collect wedges of data from multiple crystals, we were able to obtain diffraction data key to the study.”

“Alongside our structural studies, we adopted a high-throughput screening approach to identify compounds that could be promising candidates for drug development against LMTK3. To achieve this, we analyzed 28,716 small-molecule inhibitors using a wide range of biochemical, biophysical, and cell-based assays (Fig. 3),” the article states. “Herein, we report the first tool compound, namely C28, which binds to and inhibits LMTK3 (ATP-competitive inhibitor) with high selectivity and demonstrates effective anticancer effects in a variety of cancer cell lines and in in vivo BC mouse models, apparently sparing the normal epithelium.” 

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