The August edition of Small Molecules of the Month, features a recently approved, dibasic oral kallikrein inhibitor, a spirocyclobutene-containing FXR agonist, a NaV1.6 clinical candidate, a remarkably long acting RIPK2 PROTAC, and several other interesting clinical candidates.

Thanks to reviewers Joachim Rudolph, Kim Huard, Jake Schwarz, Julien Lefranc, and Chris Gampe, for their extra commentary this month.

Links to articles, PDF download, and full summaries below.

Small Molecules of the Month - Aug. 2021

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  1. The Biocryst oral plasma kallikrein inhibitor, berotralstat (BCX7353), was recently approved as the first non-steroidal treatment for prevention of hereditary angioedema attacks. The molecule is given orally (150 mg QD) despite having two basic amines. Interestingly for a chronically administered drug, the molecule is noted to have QT prolongation risk at ~3x the recommended dose (450 mg), which appears acceptable for this rare and underserved indication. The molecule was discovered after a structure-based drug design campaign starting with knowledge from a previously poorly bioavailable benzamidine-containing zwitterion, avoralstat (BCX4161). The benzamidine was successfully replaced with a similarly basic benzylamine, and the new benzylamine-containing fragment was elaborated into molecule with a highly dissimilar structure and binding mode from the original drug. There are several interesting features from the crystal structures including the fact that the highly hydrophilic primary amine is buried in a polar cleft of the protein. This approved drug is another great example of a “rule-breaker” succeeding in a rare disease setting.
  2. The GSK RIPK2 PROTAC, “compound 20”, demonstrates in vivo degradation of RIPK2 over 60 days after a single compound dose when administered SC in slow-release PLGA microparticles. This degrader was previously highlighted as a Molecule of the Month, voted by our readers as a final contender for Molecule of the Year in 2020 thanks to its remarkable in vivo PD. This article shares more details about the optimization campaign and identification of the molecule, as well as proof-of-concept on the use of the slow-release matrix, and is worth a read for all interested in targeted protein degradation.
  3. The Celgene/BMS PKCθ kinase inhibitor, CC-90005, highlighted by Julien Lefranc, is a clinical candidate in Ph. I for psoriasis, with some dosing being conducted in healthy volunteers. The safety profile is impressive given how fraught with selectivity issues previous PKC inhibitors have been. The molecule is >550-fold selective for PKCθ over PKCδ, and has relatively high sp3 character for a kinase inhibitor. The advancement of a PKC kinase inhibitor into healthy volunteers and with an intended chronic inflammation indication is testament to how far kinase inhibition has come in 20 years with respect to achievable selectivity and safety.
  4. The Astex ERK1/2 kinase inhibitor, ASTX029, is an oral Ph. I-II candidate for patients with advanced solid tumors. The molecule was derived from fragment screening together with structure-based design. Interestingly, the molecule also blocks the phosphorylation/activation of ERK1/2 in addition to inhibiting its kinase activity, making it potentially more effective. Addressing CYP3A4-mediated metabolism while maintaining favorable physicochemical properties was a key aspect of lead optimization. Though metabolism studies highlighted the oxan ring as a key site of metabolism in lead molecule, the sp3-rich moiety was necessary for potency and physicochemical properties. It was found that replacement of a different region of the molecule improved stability, demonstrating that oxan metabolism is context dependent and serving as another example of a molecule having decent half-life despite having an ether moiety. It will be interesting to see whether the different MoA of this ERK1/2 inhibitor improves the therapeutic index relative to traditional ERK1/2 kinase inhibitors.
  5. The Takeda cholesterol 24-hydroxylase inhibitor, soticlestat (TAK-935, previously OV935) is a potent, highly selective, first-in-class inhibitor of the brain-specific enzyme cholesterol 24-hydroxylase (CH24H). Cholesterol 24-hydroxylase converts cholesterol to 24S-hydroxycholesterol, which acts as a positive allosteric modulator of N-methyl-D-aspartate (NMDA) receptors. Soticlestat blocks 24S-hydroxycholesterol production in the brain in an in vivo mouse model in a dose-dependent manner (1, 3, and 10 mg/kg). It is in Ph. III as a novel anti-epileptic, for pediatric epilepsies such as in Dravet syndrome and Lennox-Gastaut syndrome. The compound (IC50 = 7.4 nM) came from 4-arylpyridine derivatives identified in a high-throughput screening (HTS) campaign with further optimization utilizing structure based drug design (SBDD). Reviewer Jake Schwarz says, “Inhibition of cholesterol metabolism to 24HC in the brain is a really interesting mechanism. At the ACS MEDI First Time Disclosures session on August 25, 2021 Al Robichaud from Sage Therapeutics disclosed the structure of neurosteroid SAGE-718, a potentiator of NMDA receptor activity for Huntington’s Disease. They used 24HC as a starting point for lead optimization. So here you have two seemingly orthogonal approaches, namely reduction of 24HC through inhibition of CH24H for epilepsies (Takeda), vs. enhancing brain levels of a 24HC mimic for treatment of HD, a rare inherited neurodegenerative disorder (Sage).”
  6. The BMS spirocyclobutene-containing FXR agonist, BMS-986318, appears to have been intended as a clinical candidate, but was withdrawn from a planned Ph. I study. The molecule exhibits potent in vitro and in vivo activation of FXR (FXR Gal4 reporter EC50 = 53 nM, SRC-1 recruitment assay EC50 = 350 nM) and demonstrates efficacy in the mouse bile duct ligation model of liver cholestasis and fibrosis. This novel molecule displayed robust target engagement in vivo and is a rare example of a cyclobutene-containing, rationally designed drug-like molecule.
  7. The Takeda MAGL inhibitor, “compound 4f”, was selected by reviewer Joachim Rudolph. “MAGL (monoacylglycerol lipase) is implicated in neuroinflammation, and inhibitors of this enzyme are of interest as therapeutics in neurodegenerative and other neurological diseases. Most of the advanced compounds, including the clinically evaluated ABX-1431, are irreversible inhibitors, but chronic blockade has been found to lead to undesirable desensitization. There is therefore a need for potent, selective reversible inhibitors of MAGL to assess their clinical viability as an alternative to irreversible inhibitors. This work by Takeda scientists reports new potent reversible MAGL inhibitors with good in vivo PK and PD profiles. The chemical structure of the lead 4f and related compounds also use interesting cyclobutyl/azetidine spiro scaffolds.” The molecule started from an HTS hit and was advanced using structure-based drug design. Compound 4f shows good oral absorption, blood-brain-barrier penetration, and significant PD at 0.3-10 mpk PO in mice which correlated with drug brain concentrations.
  8. The Merck CETP inhibitor backup, MK-8262, is potential best-in-class CETP inhibitor, which was only discontinued as a backup due to the success of its predecessor, anacetrapib in Ph. III. Reviewer Kim Huard thought this CETP inhibitor was a great piece of work from Merck, and is a great example how to deal with a very lipophilic binding site, optimizing total rather than unbound exposure and using TPSA as a surrogate for lipophilicity since the molecules were outside the reliably measurable range for LogD. “I also liked their strategy of adding a carboxylic acid to reduce lipophilicity while shifting non-specific binding from tissue towards plasma proteins,” which likely contributes to the long half-life observed. MK-8262 completed a Ph. I study in healthy volunteers and was found to be safe and likely fully efficacious at the very low projected dose of <1 mg QD.
  9. The Zentalis Wee1 inhibitor, ZN-c3, is a highly selective kinase inhibitor that is currently being evaluated in Ph. II clinical trials in adult women with recurrent or persistent uterine serous carcinoma (USC). The starting pyrazolopyrimidinone series was from the WO2013126656 patent, and while the molecule is similar to other kinase inhibitors (e.g. adavosertib, AZD1775), the ethyl group of the tertiary alcohol provided an unexpected improvement of potency while allowing maintenance of other properties including intrinsic clearance. It is an interesting example of navigating tight IP space to find a development candidate.
  10. The Bayer DNA-PK inhibitor, BAY-8400, is an orally active and selective DNA-PK kinase inhibitor that synergistically enhances the efficacy of radiotherapeutics in xenograft models. The program started with a campaign to identify ATR inhibitors, which resulted in hits against ATR, ATM, and DNA-PK, all of which are of interest due to their roles in DNA damage repair. It will be interesting to watch this active space to see whether ATR, ATM, or DNA-PK inhibition can improve therapeutic indexes or efficacy of various DNA-damaging treatments clinically.
  11. The Xenon NaV1.6 Inhibitor, NBI-921352, is remarkably selective for the NaV1.6 sodium channel over other isoforms (IC50 = 51 nM, 756x vs. NaV1.1, 134X vs. NaV1.2, 276X vs. NaV1.7, >583X vs. 1.3, 1.4, 1.5). The molecule is It is being developed to treat pediatric patients with SCN8A developmental and epileptic encephalopathy (SCN8A-DEE) and other indications such as adult focal epilepsy. The molecule is an arylsulfonamide and has a similar structure to NaV1.7 arylsulfonamide inhibitors, and is a state-dependent inhibitor, preferentially inhibiting activated channels. The molecule was well-tolerated in a Ph. I study at plasma concentrations greater than required for efficacy in preclinical studies, and efficacy will soon be evaluated in Ph. II. NBI-921352 appears to be effective in preventing seizures at lower brain and plasma concentrations than commonly prescribed sodium channel inhibitor antiseizure medicines (ASMs) carbamazepine, phenyltoin, and lacosamide, and was tolerated at higher multiples of effective plasma/brain concentrations than these prior drugs. Reviewer Jake Schwarz says, “Voltage-gated calcium channel subtypes have been studied as drug targets for decades. Only through the advent of highly subtype-selective modulators has their true therapeutic potential been revealed. Although in the case of Nav1.7, which is highly genetically validated for treatment of pain, this has not yet translated into clinically efficacious inhibitors.”
  12. The Takeda covalent BTK inhibitor clinical candidate, TAK-020, is a highly selective oral covalent BTK inhibitor with safety and tolerability profiles that are promising for both hematologic malignancies and autoimmune diseases based on a study in healthy volunteers. The molecule originated from a simple triazolone fragment, and overall is a remarkably efficient inhibitor. The triazolone fragment binds in an interesting way to the kinase with the highly polar triazolinone buried near the gatekeeper residue, likely contributing to its high kinase selectivity given that most kinases prefer more lipophilic motifs in that region. TAK-020 is anticipated to be efficacious at a very low dose (<5 mg) and it will be interesting to watch how it progresses in the highly competitive BTK landscape.
  13. The AstraZeneca oral RORgt inverse agonist, AZD0284, is an inverse agonist of the nuclear receptor RORC2 (RORγt). Reviewer Chris Gampe says, “targeting the function of Th17 cells with antibodies has been successful for the treatment of autoimmune diseases (cf. IL-17, IL-17R, IL-23 Abs). RORC2 is the transcription factor that controls Th17 function and is a small-molecule target of high interest in immunology and immuno-oncology, with at least 10 compounds in clinical development worldwide.” AZD0284 was well-tolerated in a Ph. I study with biomarker changes observed at low doses (4-238 mg). It will be interesting to see if the molecule is advanced further.
  14. The Merck KGaA MCT4 chemical probe, “compound 18n”, is a novel inhibitor of the monocarboxylate transporter MCT4. Large quantities of lactic acid need to be transported out of tumor cells due to their dependence on glucose metabolism, and this transport is mediated by MCTs. Overexpression of MCT4 is a marker for poor prognosis in cancer, and hence it has been considered as an oncology target, though tools to test the hypothesis were lacking. The Merck team found a starting point in a submicromolar hit (600 nM IC50), which was optimized to an in vivo tool compound. Unfortunately, while treatment with the MCT4 tool in combination with an MCT1/2 tool resulted in an increase in tumor lactate concentration, no significant effect on tumor growth was seen. This new tool will be helpful to help understand the role MCT4 plays in various biological contexts and whether certain tumors are more susceptible to inhibition or certain combination partners are more effective.

Links to Articles:

  1. Berotralstat (BCX7353) – Biocryst oral plasma kallikrein inhibitor
  2. “Compound 20” – GSK RIPK2 PROTAC
  3. CC-90005 – Celgene/BMS PKC-theta kinase inhibitor
  4. ASTX029 – Astex ERK1/2 clinical candidate
  5. Soticlestat – Takeda cholesterol 24-hydroxylase inhibitor
  6. BMS-986318 – BMS cyclobutene-containing FXR agonist
  7. “Compound 4f” – Takeda MAGL inhibitor
  8. MK-8262 – Merck CETP inhibitor backup
  9. ZN-c3 – Zentalis Wee1 inhibitor
  10. BAY-8400 – Bayer DNA-PK inhibitor
  11. NBI-921352 – Xenon NaV1.6 Inhibitor
  12. TAK-020 – Takeda covalent BTK inhibitor clinical candidate
  13. AZD0284 – AstraZeneca oral RORgt inverse agonist
  14. “Compound 18n” – Merck KGaA MCT4 chemical probe

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