8 minute read
Mar. 10, 2023

Drug Hunter Journal Club: February 2023

Drug Hunter Team

While the Molecules of the Month are being selected and our deep dive reviews are being prepared, you can find early highlights from our team’s journal club from February 2023.

Check out AstraZeneca’s preclinical SERD, Merck’s Ph. I c-KIT inhibitor, University of Michigan’s STAT5 PROTAC degrader, and more snippets to jumpstart your reading!

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compound 38

“Discovery of a Potent and Orally Bioavailable Zwitterionic Series of Selective Estrogen Receptor Degrader-Antagonists”
J. Med. Chem., February 1, 2023
DOI link: https://doi.org/10.1021/acs.jmedchem.2c01964 

  • Optimization of a meta-substituted series of selective estrogen receptor degrader (SERD) antagonists for the treatment of ER+ breast cancer

  • Compound 38 resulted from SBDD, modeling and NMR studies as a highly potent, basic, zwitterionic SERD

    • Degrades ERα in MCF-7 and CAMA-1 cell lines, has a clean secondary pharmacology profile, low lipophilicity and no hERG activity

    • Favorable physicochem properties resulted in good oral bioavailability in preclinical species and potent in vivo activity in mouse xenograft model

  • Review all of our SERD-related content on DH here


“Identification of M4205─A Highly Selective Inhibitor of KIT Mutations for Treatment of Unresectable Metastatic or Recurrent Gastrointestinal Stromal Tumors”
J. Med. Chem., February 2, 2023
DOI link: https://doi.org/10.1021/acs.jmedchem.2c00851

  • A common treatment strategy for gastrointestinal stromal tumors (GISTs) with activating mutations in the KIT gene is to inhibit KIT kinase

  • Treatment with TKI imatinib leads to significantly improved patient survival (for GIST), but emerging resistance and relapse has been observed

    • Several other KIT inhibitors have been approved

    • Still an unmet medical need for KIT inhibitors with high selectivity and broad coverage of clinically-relevant KIT mutants

  • HTS led to a imidazopyridine hit with very good kinase selectivity, which was optimized to Ph. I clinical candidate M4205 (IDRX-42), a class III receptor tyrosine kinase (c-KIT) inhibitor

  • M4205 has a superior profile compared to approved drugs, with best-in-class potential for recurrent and metastatic GISTs driven by KIT mutations

  • M4205 is currently in a Ph. I FIH study for advanced (metastatic and/or surgically unresectable) GISTs (NCT05489237)


“A selective small-molecule STAT5 PROTAC degrader capable of achieving tumor regression in vivo”
Nat. Chem. Bio., February 2, 2023
DOI link: https://doi.org/10.1038/s41589-022-01248-4

  • STAT5 (signal transducer and activator of transcription 5) is an attractive but difficult-to-target transcription factor

  • AK-2292 is a first, potent and selective small-molecule degrader of STAT5A and STAT5B

    • Selective over STAT proteins and >6,000 non-STAT proteins

    • Induces STAT5 depletion in normal mouse tissues and human chronic myeloid leukemia (CML) xenograft tissues; also achieves tumor regression in 2 CML xenograft mouse models at well-tolerated dose schedules

    • Could be a powerful tool compound for investigating STAT5 biology and a starting point for the development of a STAT5-targeted therapy

  • The ROCK2 kinase is upstream STAT5; see additional DH coverage on belumosudil


“Discovery of a Novel Potent and Selective HSD17B13 Inhibitor, BI-3231, a Well-Characterized Chemical Probe Available for Open Science”
J. Med. Chem., February 2, 2023
DOI link: http://dx.doi.org/10.1021/acs.jmedchem.2c01884

  • Hydroxysteroid 17ß-dehydrogenase 13 (HSD17B13): potential new target for nonalcoholic steatohepatitis (NASH) and other liver diseases

    • Physiological function and substrate of HSD17B13 are unknown, no chemical probe 

  • BI-3231 (compound 45): novel potent and selective inhibitor of HSD17B13

    • From optimization of hit from an HTS with estradiol as substrate

    • Functional, physicochemical, drug metabolism, and PK properties, and NAD+ dependency were determined

    • Probe BI-3231 will be available for free via the opnMe platform (Open Science), for the further investigation of HSD17B13 pharmacology


“CDK4/6 inhibition enhances SHP2 inhibitor efficacy and is dependent upon restoration of RB function in malignant peripheral nerve sheath tumors”
bioRxiv, February 3, 2023
DOI link: https://doi.org/10.1101/2023.02.02.526674 

  • Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive soft tissue sarcomas with limited treatment options

  • TNO155: Ph. I SHP2 inhibitor (NCT04000529) that demonstrates anti-tumor efficacy and well-tolerability in patient-derived models of MPNST when in combination with a CDK4/6i 

    • CDK4/6i = ribociclib, enhances retinoblastoma 1 (RB) activity

  • Synergistically inhibits the cell cycle and induction of apoptosis, produces additive antiproliferative and anti-tumor effects in vitro and in vivo patient-derived xenograft (PDX) models of NF1-MPNST, relative to either as a single agent

    • TNO155 attenuates the adaptive response to the CDK4/6i, greater suppression of cell cycle and inhibitor-of-apoptosis proteins, causing deeper and more durable anti-tumor activity

  • Study provides timely evidence to support the clinical advancement of this combination strategy in patients with MPNST and other tumors driven by loss of NF1

  • Nice example of a new use for SHP2 inhibitors currently pursued in combination with KRASi; for additional SHP2 DH coverage on DH, see link here

compound 31

“Discovery of a Series of Substituted 1H-((1,2,3-Triazol-4-yl)methoxy)pyrimidines as Brain Penetrants and Potent GluN2B-Selective Negative Allosteric Modulators”
J. Med. Chem., February 9, 2023
DOI link: http://dx.doi.org/10.1021/acs.jmedchem.2c01916

  • Explores a series of substituted 1H-((1,2,3-triazol-4-yl)methoxy)pyrimidines: several 5- and 6-membered heterocycles led to the identification of O-linked pyrimidine analogs with balanced potency and desirable ADME profiles

  • Compound 31: GluN2B-selective negative allosteric modulator (NAM), profiled in an ex vivo target engagement study in rats at a 10 mg/kg oral dose and achieved an ED50 of 1.7 mg/kg

    • Demonstrated high GluN2B receptor affinity, improved solubility, and clean cardiovascular profile

  • Early metabolite studies were leveraged to avoid undesired metabolic saturation

  • Janssen has taken GluN2B molecules into the clinic previously: JNJ-63612445


“Discovery and Characterization of BAY-805, a Potent and Selective Inhibitor of Ubiquitin-Specific Protease USP21”
J. Med. Chem., February 9, 2023
DOI link: https://doi.org/10.1021/acs.jmedchem.2c01933

  • USP21: in the USP subfamily of DUBs, associated with tumor development and growth, potential therapeutic target for cancer treatment

  • HTS and SBDD resulted in BAY-805: the first potent and selective, non-covalent USP21 inhibitor, and high-quality in vitro chemical probe for further exploration of USP21 biology

    • Low nanomolar affinity for USP21, high selectivity over other DUB targets and kinases, proteases, and other common off-targets

    • High-affinity target engagement of BAY-805 by SPR and CETSA, strong NF-κB activation (cell-based reporter assay)


“Disruption of Ovarian Cancer STAT3 and p38 Signaling with a Small-Molecule Inhibitor of PTP4A3 Phosphatase”
JPET, February 23, 2023
DOI link: https://doi.org/10.1124/jpet.122.001401

  • Protein tyrosine phosphatase type IVA member 3 (PTP4A3 or PRL-3) is a nonreceptor, oncogenic, dual-specificity phosphatase, highly expressed in ovarian cancer and associated with a poor patient prognosis

  • PTP4A3 directly dephosphorylates SHP-2 phosphatase (STAT3-PTP4A3 feedforward loop) and p38 kinase. 

  • Investigated the effect of JMS-053 on ovarian cancer STAT3, SHP-2, and p38 kinase phosphorylation

    • Causes an in vitro concentration- and time-dependent decrease in Y705 phospho-STAT3 (activated STAT3) in ovarian cancer cells 

    • Phosphorylation rapidly increased for SHP-2 phosphatase and p38 kinase (direct PTP4A3 substrates)

    • JMS-053-resistant A2780 and OVCAR4 cells had a 95% and 50% decrease in basal Y705 phospho-STAT3 (respectively), and were not cross-resistant to paclitaxel, cisplatin, or teniposide

    •  JMS-053–resistant OVCAR4 cells had an attenuated phosphorylation and migratory response to acute exposure to JMS-053. 

  • The combined results support a PTP4A phosphatase regulatory role in ovarian cancer cell STAT3 and p38 signaling circuits


“Alleviation of arthritis through prevention of neutrophil extracellular traps by an orally available inhibitor of protein arginine deiminase 4”
Sci. Rep., February 23, 2023
DOI link: https://doi.org/10.1038/s41598-023-30246-2

  • Protein arginine deiminases (PAD) 4 catalyzes protein citrullination and has become an attractive therapeutic target for auto-immune and inflammatory diseases

    • POC for PAD4’s role in inflammation has been established through clinical genetics and gene knockout studies in mice, and studies of PAD4-deficient mice have shown that PAD4 deficiency does not cause increased infection or immune suppression

    • PAD4 promotes chromatin decondensation and NET formation, which are associated several immune-mediated pathological conditions

    • RA has been clinically associated with PAD4

  • JBI-589 is an oral, selective and noncovalent protein arginine deiminase 4 (PAD4) inhibitor with its binding mode captured at 2.88 Å resolution by X-ray crystallography

    • In vivo efficacy was demonstrated in two mouse RA models

    • Results suggest that JBI-589 may treat both PAD4 and NET-associated pathological conditions


“Development of a Covalent Inhibitor of c-Jun N-Terminal Protein Kinase (JNK) 2/3 with Selectivity over JNK1”
J. Med. Chem., February 24, 2023
DOI link: https://doi.org/10.1021/acs.jmedchem.2c01834

  • c-Jun N-terminal kinases (JNKs) 1, 2, and 3 are members of the MAPK family

  • JNK1 and 2 have similar ATP binding pockets, but different activities: JNK2 favors cell survival and JNK1 stimulates apoptosis

  • Describes the discovery of YL5084 as covalent inhibitor with 20-fold higher Kinact/KI for JNK2 over JNK1

    • Leverages a more novel approach of targeting remote cysteines outside the ATP-binding pocket (Cys116 of JNK2) to confer selectivity over other isoforms or related targets

    • Engaged JNK2 but also exhibited JNK2-independent antiproliferative effects in multiple myeloma cells (suggests additional relevant targets)

    • A useful chemical start for probe development for the exploration of JNK biology

  • See additional DH content around JNK here

  • For another example of a remote cysteine-targeting approach in MOTM, see here.

compound 7

“Discovery of Orally Bioavailable FGFR2/FGFR3 Dual Inhibitors via Structure-Guided Scaffold Repurposing Approach”
ACS Med. Chem. Lett., February 28, 2023
DOI link: https://pubs.acs.org/doi/10.1021/acsmedchemlett.3c00003

  • Fibroblast growth factor receptors (FGFRs) are transmembrane receptor tyrosine kinases

  • Aberrant FGFR2/3 activation has been linked to cholangiocarcinoma and bladder cancer pathogenesis

  • Isoform-specific FGFR2/3 inhibitors could offer a favorable toxicity profile and improved therapeutic window, as FGFR1/4 inhibition has been linked to adverse effects

  • The discovery of dual FGFR2/FGFR3 inhibitors is disclosed, starting with scaffold hopping from a ALK2 tool compound and optimization by SBDD

  • Compound 7 is an FGFR2/3-selective and orally bioavailable inhibitor with equipotent activity toward WT and a clinically observed gatekeeper mutant

  • See additional DH content for a more extensive overview of FGFR inhibitors: futibatinib (TAS120), infigratinib, pemigatinib, compound 29, RLY–4008, ASP5878, roblitinib 


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