Volume 91 Issue 16 | p. 13
Issue Date: April 22, 2013

Cover Stories: Drug Candidates

BMS-906024, Notch Signaling Inhibitor

Department: Science & Technology | Collection: Life Sciences
News Channels: Biological SCENE, Organic SCENE
Keywords: drug discovery, medicinal chemistry, organic chemistry, cancer, melanoma, cholesterol, COPD, ACS Meetings, pharma, biotech
(From left, front row) Gavai, Weifeng Shan, (second row) Aaron Balog, Patrice Gill, Gregory Vite, (third row) Francis Lee, Claude Quesnelle, (rear row) Wen-Ching Han, Richard Westhouse.
Credit: Catherine Stroud Photography
(From left, front row) Gavai, Weifeng Shan, (second row) Aaron Balog, Patrice Gill, Gregory Vite, (third row) Francis Lee, Claude Quesnelle, (rear row) Wen-Ching Han, Richard Westhouse.
Credit: Catherine Stroud Photography

For some disease targets, an indirect approach may be best. Or so Ashvinikumar V. Gavai and his colleagues at Bristol-Myers Squibb found in their quest toward a potential cancer drug. Gavai unveiled BMS-906024, which is an experimental—and slightly roundabout—treatment for a number of cancers, including breast, lung, and colon cancers, and leukemia.

Cancers have a tendency to relapse or to become resistant to treatments that once worked. Research at BMS and elsewhere had suggested that a family of proteins called Notch is implicated in that resistance and in cancer progression more generally. Gavai, director of oncology chemistry at BMS in Princeton, N.J., and his team set out to block Notch family signaling.

Notch family members lack enzymatic activity, so blocking them directly is difficult. Instead, BMS developed inhibitors of an enzyme that is essential for activating Notch signaling—γ-secretase.


Company: Bristol-Myers Squibb

Target: pan-Notch

Disease: breast, lung, colon cancer; leukemia

Interfering with Notch, even in this indirect way, can have detrimental effects on the gastrointestinal tract. Only two of the four Notch family members are linked to that side effect, Gavai says. But he and his team think their drug will be most effective if it acts on all four family members roughly equally—a so-called pan-Notch inhibitor. By selecting a molecule that’s well tolerated in animals and carefully scheduling doses of the drug in humans, it could be possible to minimize side effects, he says.

The BMS team relied on Notch signaling assays in leukemia and breast cancer cell lines to find leads. They soon learned that for their molecules to work, three chiral centers had to be in the S,R,S configuration. After that, they strove to make the molecules last in the bloodstream. They removed an isobutyl group and tweaked some other parts of their candidate’s succinamide side chain. It was tough to retain both a long half-life and activity against Notch, Gavai told C&EN. “You’d optimize one and lose the other.”

His team threaded the needle with BMS-906024. Their studies with mice suggest that a dose of 4–6 mg once a week could be effective in people. That’s lower than doses being tested for other Notch-targeted agents, according to the website clinicaltrials.gov. The mouse studies also back the idea that Notch is involved in cancer drug resistance and suggest that Notch could be a target for taking on cancer stem cells, which are notoriously resistant to chemotherapy.

BMS-906024 is in Phase I clinical trials, both alone and in combination with other agents. Patients with colon, lung, breast, and other cancers are receiving intravenous doses of the compound to determine its safety and optimum dose ranges.

Chemical & Engineering News
ISSN 0009-2347
Copyright © American Chemical Society
Brian McMillen (Mon Apr 29 10:26:03 EDT 2013)
Were not gamma-secretase inhibitors tested in Alzheimer's patients and found to be too toxic? Something to do with myelin processing as I recall.
vignesh (Thu Jun 13 22:18:49 EDT 2013)
in diabetic foot ulcer notch signaling is uncontroled wther this inhibitor works on diabetic wound healing as aperpheral aplication
Corine Glineur (Fri Jul 26 05:05:16 EDT 2013)
What is the solubility characteristics of this product. Is it soluble in water and at which concentration? What is the EC50 of the product? Is it available for experiments in research laboratory? I am interested to test in mice to reduce lung inflammation. Thank you for your answer
cinquini (Mon Jun 15 07:28:39 EDT 2015)
my son has an adenoid kystic carcinoma with notch activation he has been in a notch inibitor trial and after 6 month resiatance appears to the treatment have you some idea about these resiatance
thanks for help
John  (Wed Sep 30 21:56:35 EDT 2015)
Cinquini, what is your email ? I'd be happy to share the information I have gathered about notch inhibitors .
Ana Abad (Fri Jul 01 18:52:59 EDT 2016)
Dear sir,
My nephew is affected by a eraly, refractaire T cell acute leukemia
I would like to know the results with NOTCH inhibitors in this kind of leukemia.
I am looking forward to hearing from you.
Yours faithfully
Ana Abad
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