If you have an ACS member number, please enter it here so we can link this account to your membership. (optional)

ACS values your privacy. By submitting your information, you are gaining access to C&EN and subscribing to our weekly newsletter. We use the information you provide to make your reading experience better, and we will never sell your data to third party members.



New drug candidates shine in San Diego

First-time disclosures symposium spotlights the process of developing clinical candidates

by Bethany Halford
April 11, 2016 | A version of this story appeared in Volume 94, Issue 15

The Division of Medicinal Chemistry’s “First-Time Disclosures” symposium, where pharmaceutical companies unveil the structures of their clinical candidates, always draws a crowd. The symposium at the ACS national meeting in San Diego last month was no exception. Hundreds of attendees packed into a convention center room to get a peek at eight new drug candidates from seven different companies. Here, we feature the structures and some of the details presented.


Structure of AZD7594.

Company: AstraZeneca

Target: Glucocorticoid receptor: When activated, this receptor regulates the expression of genes involved in the body’s immune system. Modulating it can reduce the inflammatory response that causes asthma.

Disease: Asthma, chronic obstructive pulmonary disorder (COPD)

Notes: This nonsteroidal compound is based on an earlier clinical candidate, AZD5423, which has the same indazole ether core. AZD7594, however, sits differently in the receptor’s binding pocket so that it may access a cavity where it takes advantage of polar interactions, reported Martin Hemmerling, a principal scientist with AstraZeneca.


Structure of VX984.

Company: Vertex Pharmaceuticals

Target: Catalytic subunit of DNA-dependent protein kinase: This enzyme’s subunit interacts with the protein Ku to repair double-stranded DNA breaks. Blocking the interaction can enhance the efficacy of cancer treatments that induce this type of DNA damage.

Disease: Cancer

Notes: An earlier version of VX984 with hydrogens instead of deuteriums was metabolized too quickly, rendering it less effective. So Vertex scientists used deuterium to block metabolism by the enzyme aldehyde oxidase after classical medicinal chemistry approaches, such as adding steric bulk or replacing the protons that were being oxidized, yielded inferior compounds. Putting the deuterium in place of the hydrogen should slow aldehyde oxidase via the kinetic isotope effect, said John Maxwell, Vertex’s director of medicinal chemistry.


Structure of BMS986120.

Company: Bristol-Myers Squibb

Target: Protease-activated receptor 4 (PAR4): PAR4 triggers human platelet activation via coagulation of the enzyme thrombin. So a compound that blocks PAR4 activity should prevent blood clots that form in patients with a condition known as thrombosis.

Disease: Thrombosis

Notes: Much of the work in this area has focused on family member PAR1, but recent work at BMS has validated PAR4 as an antithrombic drug target, making BMS986120 a first-in-class PAR4 antagonist, said Scott Priestley, senior principal scientist at BMS.


Structure of PF06650833.

Company: Pfizer

Target: Interleukin-1 receptor associated kinase 4 (IRAK4): This kinase is important in innate immunity, and its inhibition is predicted to be beneficial in treating inflammatory diseases.

Disease: Rheumatoid arthritis, inflammatory bowel disorder

Notes: PF06650833 came from a screening assay that used nuclear magnetic resonance spectroscopy to determine binding between molecular fragments and IRAK4. The initial hit, which bound weakly to IRAK4, was optimized with structure- and property-based medicinal chemistry to generate a series of potent inhibitors, said Katherine Lee, an associate research fellow at Pfizer.


Structure of PF06650808.

Company: Pfizer

Target: Neurogenic locus notch homolog protein 3 (NOTCH3): Activation and mutation of the NOTCH signaling pathway can lead to cancer.

Disease: Cancer

Notes: PF06650808 is an antibody-drug conjugate that delivers a cytotoxic payload molecule directly to tumor cells, explained Andreas Maderna, an associate research fellow at Pfizer. The payload molecule in PF06650808 was inspired by the marine natural product dolostatin 10, which is produced by cyanobacteria consumed by a type of sea slug.


Structure of GLPG1690.

Company: Galapagos

Target: Autotaxin: This lysophospholipase enzyme is involved the production of bioactive lipid lysophosphatidic acid and has been reported as playing a role in several lung diseases.

Disease: Idiopathic pulmonary fibrosis, a lung tissue-scarring condition

Notes: GLPG1690 will soon be entering Phase II clinical trials for idiopathic pulmonary fibrosis, reported Nicolas Desroy, team leader for medicinal chemistry at Galapagos.


Structure of GDC0853.

Company: Genentech

Target: Bruton’s tyrosine kinase (BTK): This enzyme is important in B cell maturation and in regulating cells’ production of inflammatory compounds called cytokines, making it an attractive target for immunological disorders.

Disease: Rheumatoid arthritis, lupus

Notes: GDC-0853 appears to be active against a BTK mutant that researchers have identified in cancer patients who have relapsed on Imbruvica (ibrutinib), another drug that targets BTK. This suggests the compound could also be used in these cancer patients, noted Wendy Young, Genentech’s vice president of discovery chemistry.


Structure of LY2922470.

Company:Eli Lilly & Co.

Target: G protein-coupled receptor 40 (GPR40): Also known as free fatty acid receptor 1, this protein is highly expressed in insulin-producing cells in the pancreas, called beta cells. When activated, this receptor leads to insulin secretion.

Disease: Type 2 diabetes

Notes: LY2922470 works with glucose to stimulate insulin secretion in animal models, reported Chafiq Hamdouchi, a senior research adviser at Lilly.



This article has been sent to the following recipient:

Chemistry matters. Join us to get the news you need.