SMAC mimetic
Inventors
Condon, Stephen M. • Deng, Yijun • Laporte, Matthew G. • Rippin, Susan R.
Assignees
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Publication Number
US-11351221-B2
Publication Date
2022-06-07
Expiration Date
Abstract
A SMAC mimetic and pharmaceutical compositions thereof and methods of use.
Core Innovation
The document describes a SMAC mimetic designated as Compound 15 having a defined structure in which R5 is —CH2CH3, together with pharmaceutically acceptable salts of the SMAC mimetic and pharmaceutical compositions comprising the SMAC mimetic or its pharmaceutically acceptable salts. The SMAC mimetic is described in the context of inhibiting IAPs, including Inhibitors of Apoptosis Proteins such as XIAP, cIAP-1, cIAP-2, and ML-IAP, based on SMAC/DIABLO biology.
The document states that the SMAC mimetic is useful for treating proliferative disorders, including cancer, and induces apoptosis in cells. The background and summary link the SMAC/DIABLO–IAP interaction to apoptosis regulation and describe the therapeutic goal of promoting apoptosis in cells.
The document further describes the SMAC mimetic as optionally usable in combination with other cancer therapies, including radiotherapy, chemotherapy, immunotherapy, and photodynamic therapy. It also describes use as a chemopotentiating agent and potentiation in combination with topoisomerase inhibitors of type I and type II, NSAIDs, platinum compounds, and TRAIL/TNFα-related approaches.
The document provides synthesis and characterization details for deacetylated/modified biindolyl-pyrrolidine ester/amides, identified as compounds 28, 29, 30, 31, and 32, and describes deuterated biindolyl–pyrrolidine/carbamate ester intermediates and final compounds labeled 17 through 30. The work includes coupling to a biindolyl core, deprotection steps, hydrogenolysis, and maintenance of deuteration at labeled positions, with NMR, LCMS, MS, and yield reporting.
Claims Coverage
The partial claims content includes two independent claims, covering treating cancer in a mammal and inducing apoptosis in a cancer cell, each in combination with a topoisomerase class I inhibiting compound. Across the dependents, the claims enumerate specific class I topoisomerase inhibitors and restrict the cancer/cancer cell types to small cell lung cancer or colon cancer.
Treating cancer in a mammal with a Formula (I) compound and a topoisomerase class I inhibiting compound
A method of treating cancer in a mammal includes administering an effective amount of a compound of Formula (I), wherein R5 is CH2CH3, or a pharmaceutically acceptable salt thereof, together with a topoisomerase class I inhibiting compound.
Inducing apoptosis in a cancer cell with a Formula (I) compound and a topoisomerase class I inhibiting compound
A method of inducing apoptosis in a cancer cell includes contacting the cancer cell with a compound of Formula (I), wherein R5 is CH2CH3, or a pharmaceutically acceptable salt thereof, together with a topoisomerase class I inhibiting compound.
The claim coverage requires a Formula (I) compound (R5 = CH2CH3, or a pharmaceutically acceptable salt) in combination with a topoisomerase class I inhibiting compound, with independent coverage of both in vivo cancer treatment and in vitro apoptosis induction. Dependent claims further enumerate specific topoisomerase class I inhibitors including irinotecan, SN-38, camptothecin, exatecan, grimatecan, and topotecan, and limit the target to small cell lung cancer or colon cancer.
Stated Advantages
Improved therapeutic index for Compound 15 relative to other analogs.
Treats proliferative disorders, including cancer.
Induces apoptosis in cells.
Acts as a chemopotentiating agent.
Can be used in combination with other cancer therapies, including radiotherapy, chemotherapy, immunotherapy, and photodynamic therapy.
Provides potentiation when combined with topoisomerase inhibitors (type I and type II), NSAIDs, platinum compounds, and TRAIL/TNFα-related approaches.
Documented Applications
Assessment of cIAP-1/2 degradation using a GFP-cIAP assay and related XIAP/caspase-3 derepression in the context of Example compounds 2–5 and Compound 15.
Cytotoxicity evaluation in SKOV-3 cells using MTT assay and CC50 for Example compounds 2–5 and Compound 15.
In vivo tolerability and efficacy evaluation using rat toxicity and MDA-MB-231 xenograft tumor volume reduction and weight change for Compound 15 compared with other analogs.
Treatment of proliferative disorders, including cancer.
Inducing apoptosis in cells.
Chemopotentiating use in combination with topoisomerase inhibitors (type I and type II).
Potentiation in combination with NSAIDs.
Potentiation in combination with platinum compounds.
Potentiation in TRAIL/TNFα-related approaches.
Combination use with radiotherapy, chemotherapy, immunotherapy, and photodynamic therapy.
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