Discovery of a Series of Orally Bioavailable Androgen Receptor Degraders for the Treatment of Prostate Cancer.

Androgen receptor (AR) signaling plays a key role in the progression of prostate cancer. This study describes the discovery and optimization of a novel series of AR PROTAC degraders that recruit the Cereblon (CRBN) E3 ligase. Having identified a series of AR ligands based on 4-(4-phenyl-1-piperidyl)-2-(trifluoromethyl)benzonitrile, our PROTAC optimization strategy focused on linker connectivity and CRBN ligand SAR to deliver potent degradation of AR in LNCaP cells. This work culminated in compounds 11 and 16 which demonstrated good rodent oral bioavailability. Subsequent SAR around the AR binding region brought in an additional desirable feature, degradation of the important treatment resistance mutation L702H. Compound 22 (AZ'3137) possessed an attractive profile showing degradation of AR and L702H mutant AR with good oral bioavailability across species. The compound also inhibited AR signaling in vitro and tumor growth in vivo in a mouse prostate cancer xenograft model.

Design of a Lead-Like Cysteine-Targeting Covalent Library and the Identification of Hits to Cys55 of Bfl-1.

Covalent hit identification is a viable approach to identify chemical starting points against difficult-to-drug targets. While most researchers screen libraries of <2k electrophilic fragments, focusing on lead-like compounds can be advantageous in terms of finding hits with improved affinity and with a better chance of identifying cryptic pockets. However, due to the increased molecular complexity, larger numbers of compounds (>10k) are desirable to ensure adequate coverage of chemical space. Herein, the approach taken to build a library of 12k covalent lead-like compounds is reported, utilizing legacy compounds, robust library chemistry, and acquisitions. The lead-like covalent library was screened against the antiapoptotic protein Bfl-1, and six promising hits that displaced the BIM peptide from the PPI interface were identified. Intriguingly, X-ray crystallography of lead-like compound 8 showed that it binds to a previously unobserved conformation of the Bfl-1 protein and is an ideal starting point for the optimization of Bfl-1 inhibitors.

Discovery of AZD4747, a Potent and Selective Inhibitor of Mutant GTPase KRASG12C with Demonstrable CNS Penetration.

The glycine to cysteine mutation at codon 12 of Kirsten rat sarcoma (KRAS) represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of 14, AZD4747, a clinical development candidate for the treatment of KRASG12C-positive tumors, including the treatment of central nervous system (CNS) metastases. Building on our earlier discovery of C5-tethered quinazoline AZD4625, excision of a usually critical pyrimidine ring yielded a weak but brain-penetrant start point which was optimized for potency and DMPK. Key design principles and measured parameters that give high confidence in CNS exposure are discussed. During optimization, divergence between rodent and non-rodent species was observed in CNS exposure, with primate PET studies ultimately giving high confidence in the expected translation to patients. AZD4747 is a highly potent and selective inhibitor of KRASG12C with an anticipated low clearance and high oral bioavailability profile in humans.

Discovery of AZD4625, a Covalent Allosteric Inhibitor of the Mutant GTPase KRASG12C.

KRAS is an archetypal high-value intractable oncology drug target. The glycine to cysteine mutation at codon 12 represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of 21, AZD4625, a clinical development candidate for the treatment of KRASG12C positive tumors. Highlights include a quinazoline tethering strategy to lock out a bio-relevant binding conformation and an optimization strategy focused on the reduction of extrahepatic clearance mechanisms seen in preclinical species. Crystallographic analysis was also key in helping to rationalize unusual structure-activity relationship in terms of ring size and enantio-preference. AZD4625 is a highly potent and selective inhibitor of KRASG12C with an anticipated low clearance and high oral bioavailability profile in humans.

Switchable, Reagent-Controlled Diastereodivergent Photocatalytic Carbocyclisation of Imine-Derived α-Amino Radicals.

A reagent-controlled stereodivergent carbocyclisation of aryl aldimine-derived, photocatalytically generated, α-amino radicals possessing adjacent conjugated alkenes, affording either bicyclic or tetracyclic products, is described. Under net reductive conditions using commercial Hantzsch ester, the α-amino radical species underwent a single stereoselective cyclisation to give trans-configured amino-indane structures in good yield, whereas using a substituted Hantzsch ester as a milder reductant afforded cis-fused tetracyclic tetrahydroquinoline frameworks, resulting from two consecutive radical cyclisations. Judicious choice of the reaction conditions allowed libraries of both single and dual cyclisation products to be synthesised with high selectivity, notable predictability, and good-to-excellent yields. Computational analysis employing DFT revealed the reaction pathway and mechanistic rationale behind this finely balanced yet readily controlled photocatalytic system.

Drugging the undruggable: a computational chemist's view of KRASG12C.

In recent years, the emergence of targeted covalent inhibitors which bind to the G12C mutant of KRAS have offered a solution to this previously intractable target. Inhibitors of KRASG12C tend to be structurally complex, displaying features such as atropisomerism, chiral centres and a reactive covalent warhead. Such molecules result in lengthy and challenging syntheses, and as a consequence critical decisions need to be made at the design level to maximise the chances of success. Here we take a retrospective look into how computational chemistry can help guide and prioritise medicinal chemistry efforts in the context of a series of conformationally restricted tetracyclic quinolines.

Structure-Based Design and Pharmacokinetic Optimization of Covalent Allosteric Inhibitors of the Mutant GTPase KRASG12C.

Attempts to directly drug the important oncogene KRAS have met with limited success despite numerous efforts across industry and academia. The KRASG12C mutant represents an "Achilles heel" and has recently yielded to covalent targeting with small molecules that bind the mutant cysteine and create an allosteric pocket on GDP-bound RAS, locking it in an inactive state. A weak inhibitor at this site was optimized through conformational locking of a piperazine-quinazoline motif and linker modification. Subsequent introduction of a key methyl group to the piperazine resulted in enhancements in potency, permeability, clearance, and reactivity, leading to identification of a potent KRASG12C inhibitor with high selectivity and excellent cross-species pharmacokinetic parameters and in vivo efficacy.

Covalent inhibitors of the GTPase KRASG12C: a review of the patent literature.

Introduction: KRAS is one of the most important oncology drug targets, playing a pivotal role in the initiation and progression of many human tumors. It has long been held undruggable due to many previously failed attempts to both directly and indirectly target this challenging GTPase protein family.Areas covered: This review covers patent applications claiming inhibitors of the mutant GTPase KRASG12C that act via covalent modification of cysteine at codon 12 in the period of 2014 to the present. A total of 37 PCT applications from 9 applicants are evaluated, with the discussion organized alphabetically by assignee name.Expert opinion: The last 5 years have seen an explosion in interest around this important target with many companies aiming to capitalize on the breakthrough discovery of covalent allosteric inhibitors of the glycine to cysteine mutant form of the enzyme. The first agents from this effort have now entered clinical trials and preliminary data are encouraging with responses seen in both lung adenocarcinoma and colorectal cancer patients.

Enantioselective synthesis and application to the allylic imidate rearrangement of amine-coordinated palladacycle catalysts of cobalt sandwich complexes.

The reaction of (η(5)-(N,N-dimethylaminomethyl)cyclopentadien-yl)(η(4)-tetraphenylcyclobutadiene)cobalt with sodium tetrachloropalladate and (R)-N-acetylphenylalanine gave planar chiral palladacycle di-µ-chloridebis[(η(5)-(Sp)-2-(N,N-dimethylaminomethyl)cyclopentadienyl,1-C,3'-N)(η(4)-tetraphenylcyclobutadiene)cobalt]dipalladium [(Sp )-Me2 -CAP-Cl] in 92% ee and 64% yield. Enantiopurity (>98% ee) was achieved by purification of the monomeric (R)-proline adducts and conversion back to the chloride dimer. Treatment with AgOAc gave (Sp)-Me2-CAP-OAc which was applied to asymmetric transcyclopalladation (up to 78% ee). The (R)-N-acetylphenylalanine mediated palladation methodology was applicable also to the corresponding N,N-diethyl (82% ee, 39% yield) and pyrrolidinyl (>98% ee, 43% yield) cobalt sandwich complexes. A combination of 5 mol % of the latter [(Sp)-Pyrr-CAP-Cl] and AgNO3 (3.8 equiv) is a catalyst for the allylic imidate rearrangement of an (E)-N-aryltrifluoroacetimidate (up to 83% ee), and this catalyst system is also applicable to the rearrangement of a range of (E)-trichloroacetimidates (up to 99% ee). This asymmetric efficiency combined with the simplicity of catalyst synthesis provides accessible solutions to the generation of non-racemic allylic amine derivatives.

Regioselective, stereoselective, and conformationally controlled synthesis of (η4-tetraarylcyclobutadiene)(η5-carbomethoxycyclopentadienyl)cobalt metallocenes.

The Friedel-Crafts reaction of (η(4)-tetraphenylcyclobutadiene)(η(5)-carbomethoxycyclopentadienyl)cobalt with acid chlorides/aluminum chloride resulted exclusively in para-phenyl acylation. Both monoacylated (1.1 equiv of RCOCl/AlCl(3)) and tetraacylated products (>4 equiv of RCOCl/AlCl(3)) were synthesized. Reaction of PhCC(o-RC(6)H(4)) (R = Me, i-Pr) with Na(C(5)H(4)CO(2)Me) and CoCl(PPh(3))(3) gave predominantly (η(4)-1,3-diaryl-2,4-diphenylcyclobutadiene)(η(5)-carbomethoxycyclopentadienyl)cobalt metallocenes (1,3-[trans] vs 1,2-[cis] selectivity up to 6:1). Conformational control of Friedel-Crafts reactions on the major isomers gave exclusively para-acylation of the unsubstituted phenyl groups.