There were six small molecule candidates disclosed on Apr. 10th at AACR New Orleans 2022 at the New Drugs on the Horizon session, with another four on Apr. 11th.
The New Drugs on the Horizon session is organized by the Chemistry in Cancer Research (CICR) Working Group, this year chaired by Joachim Rudolph. Thanks to reviewer Julien Lefranc and various other contributors including CICR Steering Committee Member Ingo Hartung for sharing notes. Fascinating science all around!
Novel Drug Candidates at AACR 2022
An oral BRD9 degrader and a PDE3A-SLFN12 molecular glue clinical candidate are two of the highlights from today’s disclosures at AACR. Thanks to reviewer Julien Lefranc and others for sharing their notes with everyone! Here’s all ten small molecules:
CFT7455 (C4 Therapeutics) – a selective IKZF1/3 degrader for relapsed/refractory multiple myeloma (Ph. I/II – NCT04756726) (one of two degraders from C4 disclosed in these sessions). C4 also recently disclosed clinical data from this molecule, where they identified on-target dose-limiting toxicity, and trying to increase the therapeutic index with an alternative dosing schedule. It will be interesting to watch this as a case study for the degrader mechanism of action as alternative dosing is challenging to pull off even with non-degrader modalities.
FHD-286 (Foghorn Therapeutics) – a first-in-class, oral, allosteric BAF chromatin remodeling complex inhibitor (via BRG1 and BRM ATPase inhibition) in two Ph. I trials for metastatic uveal melanoma (NCT04879017) and advanced hematologic malignancies (NCT04891757)
GDC-6036 (Genentech) – an oral, covalent mutant KRAS G12C inhibitor in Ph. I (NCT04449874), following adagrasib and sotorasib in the class
EZM0414 (Epizyme) – a first-in-class, oral, selective inhibitor of SETD2, a histone methyltransferase ready to enter Ph. I (NCT05121103) – not yet recruiting. Preclinical data had previously been prevented at ASH 2021. Interestingly the lead scaffold is isomeric to the most recent SETD2 compound patent from Epizyme (WO2021168313)
CFT8634 (C4 Therapeutics) – received Orphan Drug Designation from the FDA, first patient in expected this year
BAY 2666605 (Bayer) – a PDE3A-SLFN12 molecular glue (“velcrin”), induces a complex with a crystal structure published in collaboration with the Broad Institute. Nice progress from a starting point (DNMDP) shared by Broad scientists and developed in collaboration with Bayer. Hope it does well in its Ph. I trial in metastatic melanoma and other solid tumors NCT04809805.
KSQ-4279 (KSQ Therapeutics, Inc.) – an allosteric, first-in-class USP1 inhibitor going into Ph. I in tumors alone and in combo with PARP inhibition. Has a reversible induced fit mechanism
ABBV-CLS-484 (AbbVie, Calico Life Sciences, Broad Institute of MIT and Harvard) – an X-ray confirmed, picomolar active-site inhibitor of phosphatase PTPN2/N1 – phosphatases typically thought of as undruggable. Going into Ph. I in combo with checkpoint inhibition. Phosphatase inhibitors has always been polar, but they managed to get this one just right!
MRTX0902 (Mirati Therapeutics) – a SOS1 inhibitor for KRAS+ cancer following Boehringer Ingelheim’s BI 1701963 – BI and Mirati previously collaborated on BI’s SOS1 inhibitor with MRTX849
NXP800 – an oral heat shock factor 1 (HSF1) pathway inhibitor with a Ph. I trial open (first-in-class); from a phenotypic screen for HSP72 activity
Additional Candidates Disclosed at AACR
There were two other noteworthy small molecule first disclosures besides the New Drugs on the Horizon candidates. These included the Novartis IKZF2 glue NVP-DKY709 and the Relay/Genentech SHP2 inhibitor RLY-1971/GDC-1971. The SHP2 compound is a potential best-in-class molecule, but was only disclosed on a poster.
Abstracts of the New Drugs on the Horizon AACR New Orleans 2022 Sessions:
Apr. 13, 2022 Update: AACR has just published a very nice recap of each lecture.
Hope this is helpful!