Kymera's KT-474 is the first oral degrader to demonstrate activity in clinical trials outside cancer and Sanofi recently started a Ph. II trial with the molecule in AD, restoring life to IRAK4 as an immunology target. This article highlights why Kymera’s KT-474 program is scientifically notable, including how it differentiates from small molecule inhibitors, potential competitiveness with biologics, the first reported cryo-EM ternary complex of a heterobifunctional degrader, and why this 2023 Molecule of the Year Nominee will likely be considered a “landmark in drug discovery” for some time.

Nurix recently unveiled their second clinical BTK degrader, NX-5948, which is in Ph. Ia/Ib for patients with advanced B-cell malignancies (NCT05131022). A novel CRBN ligand was developed to remove IKZF1/3 degradation activity, distinguishing NX-5948 from their earlier disclosed dual BTK-IKZF1/3 degrader NX-2127, which is currently in Ph. I for relapsed/refractory B-cell malignancies (NCT04830137). The potent BTK degrader NX-5948 has displayed CNS penetration preclinically, allowing for primary CNS lymphoma (PCNSL) participants to be included in the clinical study.

Targeted protein degraders continue to show differentiation from traditional small molecules in terms of both efficacy and safety. To expand the scope of targeted protein degradation (TPD), there has been significant interest throughout the industry in leveraging new E3 ligases beyond CRBN, VHL, MDM2, cIAP, and SCF.

Targeted Protein Degradation (TPD) allows for elimination, rather than inhibition, of proteins by exploiting cells’ own protein clearance mechanisms. While traditional inhibitors can be very effective at preventing a protein from undertaking a particular function, blocking protein activity...

In Wednesday’s Flash Talk webinar, we covered recent highlights in targeted protein degradation, with lots of great questions from the audience. The webinar and recording are available below to everyone thanks to our sponsor, Revvity Signals, and the slides are available for download to Premium members at the bottom.

This article highlights million-dollar molecules that were recently in the news with related patent applications that give clues to their structures and properties. This edition includes Maze’s glycogen synthase 1 (GYS1) inhibitors that were recently licensed to Sanofi, allosteric androgen receptor (AR) modulators that may be of interest to targeted protein degradation researchers, brain-penetrant HER2 and ROCK2 inhibitors, and MDM2 degraders.

CFT1946 from C4 Therapeutics is a potent, selective, and orally bioavailable bifunctional degrader of mutant BRAF in Ph. I/II for the treatment of BRAF-driven solid tumors, alone and in combo with a MEK1/2 inhibitor (trametinib) (NCT05668585). BRAF-V600X is clinically validated with approved drugs (e.g. vemurafenib), but traditional inhibitors face challenges in selectivity over wildtype BRAF and can cause paradoxical RAF activation. [...]

A second-generation AR bifunctional degrader for drug-resistant prostate cancer. ARV-766 is Arvinas’ second bifunctional CRL4 CRBN E3 ligase-based androgen receptor (AR) degrader to enter the clinic for the treatment of prostate cancer (PCa), after ARV-110 (bavdegalutamide) . The glutarimide recruiting element is notable as it is simpler than [...]

This article highlights six recent articles of interest in the field of targeted protein degradation including but not limited to potentially new ligases, recruiting motifs, and a discussion on the feasibility of CNS-penetrant degraders. 1. “Reinstating targeted protein degradation with DCAF1 PROTACs in CRBN PROTAC resistant settings” [...]

“PROTAC 6” (GlaxoSmithKline (GSK) IAP-based selective RIPK2 degrader with prolonged in vivo PD)

Tumors can evade the immune system through the recruitment of regulatory T cells (Treg) which limit the activation and expansion of effector T cells (Teff). IKZF2 (Helios) is an Ikaros transcription factor family member that is expressed in a majority of Treg cells [...]

What is it? Elacestrant ( Orserdu ) is an oral, selective estrogen receptor modulator and degrader (SERM/SERD) that was recently approved for ER-positive, HER2-negative, estrogen receptor ɑ (ESR1)-mutated advanced or metastatic breast cancer (345 mg PO QD) based on progression-free survival (PFS) data from EMERALD ( NCT03778931 ). As the [...]

Inavolisib is a PI3Kα isoform-selective kinase inhibitor and monovalent degrader of the mutant p110α catalytic subunit of mutant PI3Kα. The molecule selectively depletes mutant p110α in cancer cells with active receptor tyrosine kinase (RTK) signaling, and is in several ongoing or planned Ph. III trials for breast cancer. Recently, Genentech announced Ph. III results with the molecule showing that it could be a best-in-class treatment option for PI3Kα-driven cancers. This article explains how it works, how it was discovered, and why it matters.

Since the 2014 discoveries that thalidomide-like compounds “glue” together the cereblon (CRBN) unit of the ubiquitin E3 ligase complex and certain immune cell transcription factors, molecular glue degraders have been caught up in the targeted protein degradation zeitgeist that catapulted PROTACs , their bulkier bivalent counterparts, to the [...]

The Genentech PI3Kα isoform-selective kinase inhibitor and mutant PI3Kα degrader inavolisib selectively depletes the oncogenic mutant p110α catalytic subunit of PI3Kα in cancer cells with active receptor tyrosine kinase (RTK) signaling. The gene encoding p110α, PIK3CA, is one of the most frequently mutated oncogenes, with over 2M cancer [...]

The Arvinas ER chimeric degrader, ARV-471 , is an oral, bioavailable ER degrading CRBN-based  PROTAC for the treatment of patients with ER+/HER2- breast cancer. Along with ARV-110 , it is one of the first chimeric degraders to enter a Ph. II clinical trial. It was first disclosed at AACR in early 2021, and though the molecules have not been [...]

The Genentech XIAP E3-ligase degrader, compound 10 , has an interesting mechanism of action, triggering the degradation of its target (XIAP) by ubiquitylation of the small molecule. The molecule behaves as a lysine mimetic, accepting ubiquitin from the targeted E3 complex, promoting XIAP’s own degradation. As E3 ligases are often difficult to [...]

The bifunctional degrader, SJ995973 , was nominated by Joachim Rudolph . “Instead of the thalidomide-based cereblon binder present in the established BET degrader tool dBET1, SJ995973 uses a novel cereblon binder containing a simple phenyl ring instead of the hydrolytically labile phthalimide group. Not only is SJ995973 an extremely potent [...]

The Michigan bifunctional degrader, ARD-2585 , is similar to the Arvinas molecule, ARV-110 that was recently disclosed at AACR 2021. ARV-110 is a first-in-class, potent, and orally active AR degrader in clinical development, but understandably hasn’t had much published on it yet given the competitive environment. The publication of ARD-2585 [...]

The Bristol Myers Squibb (BMS)/Celgene GSPT1 degrader (CC-90009) is a CRBN-based molecular glue (CELMoD). It is a clinical candidate in Ph. I for AML and MDS, and in contrast to CC-92480 highlighted last March, spares the primary targets of prior imide drugs (IKZF1/3) and instead selectively degrades GSPT1 ( a target previously identified [...]

CG428 (Cullgen CRBN-based TRK kinase fusion protein degrader)

“compound 23” is a selective CRBN-based degrader of the pseudokinase, IRAK3, with in vitro activity in primary human cells. A volcano plot shows remarkable separation between IRAK3 degradation vs. most other proteins, with very little activity against family members IRAK1 and IRAK4. The authors were able to quickly generate this degrader from [...]

( R )-CR8 is a known CDK inhibitor that was recently discovered to be a molecular glue-type degrader of cyclin K. A crystal structure of an E3 component-CR8-CDK12-cyclin K complex shows that CR8 acts by binding to the active site of a CDK (which binds to cyclin K), and recruiting an E3 component through a solvent-exposed lipophilic moiety on [...]

CC-92480 (Celgene/Bristol Myers Squibb (BMS) oral in vivo CRBN-based selective IKZF1/3 degrader)

“PROTAC 6” (GlaxoSmithKline (GSK) IAP-based selective RIPK2 degrader with prolonged in vivo PD)

This post briefly introduces chimeric molecules and companies working on them, contains a list of 10 recent “hot” papers in this field, and some predictions for where chimeras might head. It’s Chinese New Year time, which means a significant part of the global biopharma supply chain has ground to a halt, due to our colleagues and suppliers in [...]