Express | Arvinas announces the molecular structure of the star PROTAC

▎The content team editor of WuXi AppTec recently, Arvinas, a company dedicated to the development of targeted protein degradation therapies, announced at the American Association for Cancer Research (AACR) annual meeting the molecular structure and Medicinal chemistry optimization process.

Arvinas’ ARV-110 and ARV-471 are PROTAC molecules under research that target the degradation of androgen receptor (AR) and estrogen receptor (ER), respectively.

Previously announced preliminary clinical trial results showed that ARV-471 showed the potential of a "best-in-class" estrogen receptor degrading agent.

In the Phase 1/2 clinical trial of ARV-110 in the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC), the prostate-specific antigen (PSA) level of 40% of patients with specific gene mutations was measured Reduce by more than 50%.

Therefore, their molecular structure and the process of drug discovery and optimization have also attracted the attention of professionals.

Targeted protein degradation is currently one of the hot areas in the development of new drugs.
By leading to the degradation of diseased proteins, protein degradation agents can provide new means to target past "unable to drug" targets.

The PROTAC therapy developed by Arvinas is a small molecule drug.
One end of it can be combined with the target protein, and the other end can be combined with E3 ubiquitin ligase.

This molecule can recruit the E3 ubiquitin ligase to the vicinity of the target protein, and label the target protein with ubiquitin.

In the cell, the protein labeled with ubiquitin will be sent to the proteasome for degradation.

In this way, PROTAC molecules can specifically promote the degradation of disease-causing proteins.

Arvinas estimates that 80% of current "non-drugable" targets can be targeted by PROTAC molecules.

▲The mechanism of the PROTAC bispecific molecule (picture source: Arvinas official website) At present, the E3 ubiquitin ligase that most protein degrading agents bind to is vonHippel-Lindau (VHL) or cereblon (CRBN) protein.

The molecular glue developed based on the lenalidomide derivative combined with CRBN is also an important research direction of protein degradation therapy.

At the AACR annual meeting, Arvinas revealed the molecular structure and medicinal chemistry optimization process of ARV-110 and ARV-471 respectively.
Please see the figure below for details.

▲The molecular structure and medicinal chemistry optimization process of ARV-110 (picture source: AACR) ▲The molecular structure and medicinal chemistry optimization process of ARV-471 (picture source: AACR) Industry experts said that these two PROTAC molecules are based on the protein with CRBN The bound molecules were further optimized and showed good activity in clinical trials.

Previously released ARV-471 clinical trial results ARV-471 can significantly reduce the ER expression level in patient tumor tissues, reducing the ER level by an average of 62%, up to nearly 90%.

Moreover, ARV-471 showed degrading effects on both wild-type ER and ER mutants.

▲ARV-471 significantly reduced the expression level of ER in tumor tissues (picture source: reference [2]) Among the 14 patients whose anti-cancer activity can be analyzed, one patient achieved confirmed partial remission, and tumor lesions shrank by 51%.

Two patients achieved unconfirmed partial remissions, and one patient had stable disease and reduced lesions by more than 50%.

Of the 12 patients who were able to assess the clinical benefit rate, 5 (42%) patients achieved clinical benefit.

It is worth mentioning that these 5 patients have previously been treated with other approved or under study estrogen receptor degrading agents.

▲Efficacy data of ARV-471 (picture source: Reference [2]) The clinical data previously released by ARV-110 among 5 patients with androgen receptor T878 or H875 mutations, 4 patients had PSA levels reduced by 30% Above, the PSA level of 2 patients decreased by more than 50%.

Arvinas said that these mutations in AR may mean that tumors are more dependent on the AR signaling pathway, and thus have a stronger response to ARV-110.

This group of patients with specific molecular biological characteristics may support the accelerated approval of ARV-110 as a precision therapy.

▲ARV-110 significantly reduces PSA levels in patients with specific gene mutations (picture source: reference [2]) At present, Arvinas has launched a phase 2 clinical trial of the dose extension of ARV-110 and ARV-471.

The company also initiated a phase 1b clinical trial to test the effects of ARV-471 in combination with the CDK4/6 inhibitor Ibrance (palbociclib).

Reference: [1] Arvinas Announces Upcoming Presentations at the American Association for Cancer Research Annual Meeting 2021.
Retrieved April 12, 2021, from /en/Arvinas-Announces-Upcoming-Presentations-at-the-American-Association-for-Cancer-Research-Annual-Meeting-2021.
html[2] Arvinas corporate presentation.
Retrieved April 12,2021, from https:// ir.
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