Orally Bioavailable Proteolysis-Targeting Chimeras: An Innovative Approach in the Golden Era of Discovering Small-Molecule Cancer Drugs.

Proteolysis-targeting chimeras (PROTACs) are an emerging therapeutic modality that show promise to open a target space not accessible to conventional small molecules via a degradation-based mechanism. PROTAC degraders, due to their bifunctional nature, which is categorized as 'beyond the Rule of Five', have gained attention as a distinctive therapeutic approach for oral administration in clinical settings. However, the development of PROTACs with adequate oral bioavailability remains a significant hurdle, largely due to their large size and less than ideal physical and chemical properties. This review encapsulates the latest advancements in orally delivered PROTACs that have entered clinical evaluation as well as developments highlighted in recent scholarly articles. The insights and methodologies elaborated upon in this review could be instrumental in supporting the discovery and refinement of novel PROTAC degraders aimed at the treatment of various human cancers.

Therapies for the Treatment of Advanced/Metastatic Estrogen Receptor-Positive Breast Cancer: Current Situation and Future Directions.

The hormone receptor-positive (HR+) type is the most frequently identified subtype of breast cancer. HR+ breast cancer has a more positive prognosis when compared to other subtypes, such as human epidermal growth factor protein 2-positive disorder and triple-negative disease. The advancement in treatment outcomes for advanced HR+ breast cancer has been considerably elevated due to the discovery of cyclin-dependent kinase 4/6 inhibitors and their combination effects with endocrine therapy. However, despite the considerable effectiveness of tamoxifen, a selective estrogen receptor modulator (SERMs), and aromatase inhibitors (AI), the issue of treatment resistance still presents a significant challenge for HR+ breast cancer. As a result, there is a focus on exploring new therapeutic strategies such as targeted protein degradation and covalent inhibition for targeting ERα. This article discusses the latest progress in treatments like oral selective ER degraders (SERDs), complete estrogen receptor antagonists (CERANs), selective estrogen receptor covalent antagonists (SERCAs), proteolysis targeting chimera (PROTAC) degraders, and combinations of CDK4/6 inhibitors with endocrine therapy. The focus is specifically on those compounds that have transitioned into phases of clinical development.

Discovery of Pyrrolo[2,3-c]pyridines as Potent and Reversible LSD1 Inhibitors.

Lysine specific demethylase 1 (LSD1) acts as an epigenetic eraser by specifically demethylating mono- and histone 3 lysine 4 (H3K4) and H3 lysine 9 (H3K9) residues. LSD1 has been pursued as a promising therapeutic target for the treatment of human cancer, and a number of LSD1 inhibitors have been advanced into clinical development. In the present study, we describe our discovery of pyrrolo[2,3-c]pyridines as a new class of highly potent and reversible LSD1 inhibitors, designed on the basis of a previously reported LSD1 inhibitor GSK-354. Among them, 46 shows an IC50 value of 3.1 nM in inhibition of LSD1 enzymatic activity and inhibits cell growth with IC50 values of 0.6 nM in the MV4;11 acute leukemia cell line and 1.1 nM in the H1417 small-cell lung cancer cell line. Compound 46 (LSD1-UM-109) is a novel, highly potent, and reversible LSD1 inhibitor and serves as a promising lead compound for further optimization.

Discovery of ERD-3111 as a Potent and Orally Efficacious Estrogen Receptor PROTAC Degrader with Strong Antitumor Activity.

Estrogen receptor α (ERα) is a prime target for the treatment of ER-positive (ER+) breast cancer. Despite the development of several effective therapies targeting ERα signaling, clinical resistance remains a major challenge. In this study, we report the discovery of a new class of potent and orally bioavailable ERα degraders using the PROTAC technology, with ERD-3111 being the most promising compound. ERD-3111 exhibits potent in vitro degradation activity against ERα and demonstrates high oral bioavailability in mice, rats, and dogs. Oral administration of ERD-3111 effectively reduces the levels of wild-type and mutated ERα proteins in tumor tissues. ERD-3111 achieves tumor regression or complete tumor growth inhibition in the parental MCF-7 xenograft model with wild-type ER and two clinically relevant ESR1 mutated models in mice. ERD-3111 is a promising ERα degrader for further extensive evaluations for the treatment of ER+ breast cancer.

Targeting the Estrogen Receptor for the Treatment of Breast Cancer: Recent Advances and Challenges.

Estrogen receptor alpha (ERα) is a well-established therapeutic target for the treatment of ER-positive (ER+) breast cancers. Despite the tremendous successes achieved with tamoxifen, a selective ER modulator, and aromatase inhibitors (AIs), resistance to these therapies is a major clinical problem. Therefore, induced protein degradation and covalent inhibition have been pursued as new therapeutic approaches to target ERα. This Perspective summarizes recent progress in the discovery and development of oral selective ER degraders (SERDs), complete estrogen receptor antagonists (CERANs), selective estrogen receptor covalent antagonists (SERCAs), and proteolysis targeting chimera (PROTAC) ER degraders. We focus on those compounds which have been advanced into clinical development.

Discovery of EEDi-5273 as an Exceptionally Potent and Orally Efficacious EED Inhibitor Capable of Achieving Complete and Persistent Tumor Regression.

Embryonic ectoderm development (EED) is a promising therapeutic target for human cancers and other diseases. We report herein the discovery of exceptionally potent and efficacious EED inhibitors. By conformational restriction of a previously reported EED inhibitor, we obtained a potent lead compound. Further optimization of the lead yielded exceptionally potent EED inhibitors. The best compound EEDi-5273 binds to EED with an IC50 value of 0.2 nM and inhibits the KARPAS422 cell growth with an IC50 value of 1.2 nM. It demonstrates an excellent PK and ADME profile, and its oral administration leads to complete and persistent tumor regression in the KARPAS422 xenograft model with no signs of toxicity. Co-crystal structures of two potent EED inhibitors with EED provide a solid structural basis for their high-affinity binding. EEDi-5273 is a promising EED inhibitor for further advanced preclinical development for the treatment of human cancer and other human diseases.

EEDi-5285: An Exceptionally Potent, Efficacious, and Orally Active Small-Molecule Inhibitor of Embryonic Ectoderm Development.

Inhibition of embryonic ectoderm development (EED) is a new cancer therapeutic strategy. Herein, we report our discovery of EEDi-5285 as an exceptionally potent, efficacious, and orally active EED inhibitor. EEDi-5285 binds to the EED protein with an IC50 value of 0.2 nM and inhibits cell growth with IC50 values of 20 pM and 0.5 nM in the Pfeiffer and KARPAS422 lymphoma cell lines, respectively, carrying an EZH2 mutation. EEDi-5285 is approximately 100 times more potent than EED226 in binding to EED and >300 times more potent than EED226 in inhibition of cell growth in the KARPAS422 cell line. EEDi-5285 has excellent pharmacokinetics and achieves complete and durable tumor regression in the KARPAS422 xenograft model in mice with oral administration. The cocrystal structure of EEDi-5285 in a complex with EED defines the precise structural basis for their high binding affinity. EEDi-5285 is the most potent and efficacious EED inhibitor reported to date.

Exploration of Ring Rearrangement Metathesis Reaction: A General and Flexible Approach for the Rapid Construction [5,n]-Fused Bicyclic Systems en Route to Linear Triquinanes.

Structurally diverse [5,n] bicyclic systems with cis ring junction stereochemistry were accessed readily through RRM (ring rearrangement metathesis) reaction of properly functionalized [2.2.1]norbornene skeletons. Several bicyclic enones, ketones, alcohols, and ethers acted as the substrates and yielded the respective linearly fused [5,n] bicyclic systems stereoselectively after the RRM reaction. Such [5,5]bicyclic enone scaffolds were then synthetically manipulated to core structural analogue of naturally occurring liner triquinane hirsutene having cis-syn-cis stereochemistry.