Small molecule degraders of estrogen receptor with cereblon ligands

http://deepblue.lib.umich.edu/bitstream/2027.42/174692/2/90911443_1663117200.pd

Cereblon ligands

The disclosure provides compds. of formula I,​and the salts and solvates thereof. The disclosure also relates to uses of the compds. as cereblon (CRBN) ubiquitination inhibitors, as synthetic intermediates that can be used to prep. PROTAC mols., or as PROTAC mols. The disclosure also relates to uses of the compds., e.g., in treating or preventing cancer and other diseases. Compds. of formula I wherein when A1 is CR2a and N; then A is CR2b; A2 is CR2c; A3 is CR2' and N; R2a and R2' are independently H, halo, C1-​3 alkyl, amino and C1-​3 alkoxy; R2bR2c are taken together to form (CH2)​1-​3 NR1a(CH2)​1-​3, (CH2)​1-​3 CR1bR1c(CH2)​1-​3, CONR1'(CH2)​1,​-​2, etc.; when A1 is CR2a and N; then A is CR2b; A2 is CR2c; A3 is CR2' and N; R2c and R2' are independently H, halo, C1-​3 alkyl, amino and C1-​3 alkoxy; R2aR2b are taken together to form (CH2)​1-​3 NR1a(CH2)​1-​3, (CH2)​1-​3 CR1bR1c(CH2)​1-​3, CONR1'(CH2)​1,​-​2, etc.; R1a is H, C1-​3 alkyl, aryl, heteroaryl, etc.; R1b is H, CHO, CO2H, NH2, etc.; R1c is H; R1bR1c may be taken together to form :O and azacycle; R1' is H, heterocyclyl, heterocycloalkyl, etc.; R3 is H, D, F and C1-​3 alkyl; Z and Z1 are CO; Z is CO and Z1 is CR4aR4b and N:C(CH3)​; Z is CR4aR4b and N:C(CH3) and Z1 is CO; Z is a bond and Z1 is NHCO and derivs.; Z is NHCO and derivs. and Z1 is a bond; R4a and R4b are independently H and C1-​3 alkyl R4aR4b may be taken together to form C3-​6 cycloalkyl; and pharmaceutically acceptable salts and solvates thereof, are claimed. Example compd. II was prepd. by a multistep procedure (procedure given)​. The invention compds. were evaluated for their cereblon binding activityhttp://deepblue.lib.umich.edu/bitstream/2027.42/175010/2/CEREBLON LIGANDS.pd

Imidazo[4,5-c]pyridine compounds as lsd-1 inhibitors

The present disclosure provides compounds represented by Formula I: and the pharmaceutically acceptable salts and solvates thereof, wherein R1, R2, R3, and R4 are as defined as set forth in the specification. The present disclosure also provides compounds of Formula I for use to treat a condition or disorder responsive to LSD1 inhibition such as cancer.http://deepblue.lib.umich.edu/bitstream/2027.42/174696/2/83996668_1574652646.pd

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.http://deepblue.lib.umich.edu/bitstream/2027.42/192163/2/cancers-16-00552-v2 (1).pdfPublished onlin

Stereoselective synthesis of a novel natural carbasugar and analogues from hydroxymethylated cycloalkenone scaffolds

http://deepblue.lib.umich.edu/bitstream/2027.42/174126/2/Stereoselective synthesis of a novel natural carbasugar and analogues.pdfPublished versio

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. Herein, we report the discovery of a new class of potent and orally efficacious ERα degraders using the PROTAC technology with ERD-3111 being the most promising compound. ERD-3111 potently and effectively induced degradation of ERα protein in ER+ MCF-7 and T47D cells. Importantly, it achieved an excellent pharmacokinetic profile in rats, mice and dogs and good oral bioavailability in these species. ERD-3111 shows excellent microsomal stability and exhibits no significant hERG or CYP inhibition. PK/PD studies demonstrated that oral administration of ERD-3111 is highly effective in reducing the levels of wild-type and mutated ERα proteins in xenograft tumor tissues and achieves high plasma and tumor tissue exposures. Consistent with effective depletion of wild-type and ERα mutated proteins in tumor tissues, ERD-3111 demonstrates strong antitumor activity and is capable of achieving persistent tumor regression in the MCF-7 ER wild-type and ESR1D538G xenograft tumor models or 100% of tumor growth inhibition in the MCF-7 ESR1Y537S mutated xenograft tumor model. Significantly, ERD-3111 treatments did not cause animal weight loss or exhibit other signs of toxicity in mice. Taken together, our data show that ERD-3111 is a potent, orally bioavailable and highly efficacious ERα PROTAC degrader, and represents a promising lead compound for extensive evaluations for the treatment of ERα+ breast cancer.http://deepblue.lib.umich.edu/bitstream/2027.42/191182/2/ICBS2023_Abstract_ERD-3111_Zhixiang Chen_University of Michigan.doc

Spiro compounds as IKZF2 degraders and their preparation, pharmaceutical compositions and use in the treatment of cancer

http://deepblue.lib.umich.edu/bitstream/2027.42/191181/2/WO 2023-183540 Al.pd

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

Structurally diverse [5,<i>n</i>] bicyclic systems with <i>cis</i> 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,<i>n</i>] 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 <i>cis</i>-<i>syn</i>-<i>cis</i> stereochemistry

Discovery of ERD3111 as a Potent and Orally Efficacious Estrogen Receptor PROTAC Degrader with Strong Antitumor Activity

http://deepblue.lib.umich.edu/bitstream/2027.42/191183/2/Poster_ERD-3111 paper.pd

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

Structurally diverse [5,<i>n</i>] bicyclic systems with <i>cis</i> 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,<i>n</i>] 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 <i>cis</i>-<i>syn</i>-<i>cis</i> stereochemistry