Alkaline phosphatase variation during carfilzomib treatment is associated with best response in multiple myeloma patients

The ubiquitin–proteasome pathway regulates bone formation through osteoblast differentiation. We analyzed variation alkaline phosphatase (ALP) during carfilzomib treatment. Data from 38 patients enrolled in the PX‐171‐003 and 29 patients in PX‐171‐004 studies, for patients with relapsed/refractory myeloma, were analyzed. All patients received 20 mg/m 2 of carfilzomib on Days 1, 2, 8, 9, 15, and 16 of a 28‐day cycle. Sixty‐seven patients from ALP data were evaluable. In PX‐171‐003, the ORR (>PR) was 18% and the clinical benefit response (CBR; >MR) was 26%, while in PX‐171‐004, the ORR was 35.5% overall and 57% in bortezomib‐naive patients. ALP increment from baseline was statistically different in patients who achieved ≥VGPR compared with all others on Days 1 ( P  = 0.0049) and 8 ( P  = 0.006) of Cycle 2. In patients achieving a VGPR or better, ALP increased more than 15 units per liter at Cycle 2 Day 1 over baseline. An ALP increase over the same period of time was seen in 26%, 13% and 11% of patients achieving PR, MR, and SD, respectively. This retrospective analysis of patients with relapsed or refractory myeloma treated with single‐agent carfilzomib indicates that early elevation in ALP is associated with subsequent myeloma response.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/86807/1/j.1600-0609.2011.01602.x.pd

A selective inhibitor of the immunoproteasome subunit LMP7 blocks cytokine production and attenuates progression of experimental arthritis

The immunoproteasome, a distinct class of proteasome found predominantly in monocytes and lymphocytes, is known to shape the antigenic repertoire presented on class I major histocompatibility complexes (MHC-I). However, a specific role for the immunoproteasome in regulating other facets of immune responses has not been established. We describe here the characterization of PR-957, a selective inhibitor of low-molecular mass polypeptide-7 (LMP7, encoded by Psmb8), the chymotrypsin-like subunit of the immunoproteasome. PR-957 blocked presentation of LMP7-specific, MHC-I-restricted antigens in vitro and in vivo. Selective inhibition of LMP7 by PR-957 blocked production of interleukin-23 (IL-23) by activated monocytes and interferon-gamma and IL-2 by T cells. In mouse models of rheumatoid arthritis, PR-957 treatment reversed signs of disease and resulted in reductions in cellular infiltration, cytokine production and autoantibody levels. These studies reveal a unique role for LMP7 in controlling pathogenic immune responses and provide a therapeutic rationale for targeting LMP7 in autoimmune disorders

12,13-Aziridinyl Epothilones. Stereoselective Synthesis of Trisubstituted Olefinic Bonds from Methyl Ketones and Heteroaromatic Phosphonates and Design, Synthesis, and Biological Evaluation of Potent Antitumor Agents

The synthesis and biological evaluation of a series of 12,13-aziridinyl epothilone B analogues is described. These compounds were accessed by a practical, general process that involved a 12,13-olefinic methyl ketone as a starting material obtained by ozonolytic cleavage of epothilone B followed by tungsten-induced deoxygenation of the epoxide moiety. The attachment of the aziridine structural motif was achieved by application of the Ess–Kürti–Falck aziridination, while the heterocyclic side chains were introduced via stereoselective phosphonate-based olefinations. In order to ensure high (<i>E</i>) selectivities for the latter reaction for electron-rich heterocycles, it became necessary to develop and apply an unprecedented modification of the venerable Horner–Wadsworth–Emmons reaction, employing 2-fluoroethoxyphosphonates that may prove to be of general value in organic synthesis. These studies resulted in the discovery of some of the most potent epothilones reported to date. Equipped with functional groups to accommodate modern drug delivery technologies, some of these compounds exhibited picomolar potencies that qualify them as payloads for antibody drug conjugates (ADCs), while a number of them revealed impressive activities against drug resistant human cancer cells, making them desirable for potential medical applications

12,13-Aziridinyl Epothilones. Stereoselective Synthesis of Trisubstituted Olefinic Bonds from Methyl Ketones and Heteroaromatic Phosphonates and Design, Synthesis, and Biological Evaluation of Potent Antitumor Agents

The synthesis and biological evaluation of a series of 12,13-aziridinyl epothilone B analogues is described. These compounds were accessed by a practical, general process that involved a 12,13-olefinic methyl ketone as a starting material obtained by ozonolytic cleavage of epothilone B followed by tungsten-induced deoxygenation of the epoxide moiety. The attachment of the aziridine structural motif was achieved by application of the Ess–Kürti–Falck aziridination, while the heterocyclic side chains were introduced via stereoselective phosphonate-based olefinations. In order to ensure high (<i>E</i>) selectivities for the latter reaction for electron-rich heterocycles, it became necessary to develop and apply an unprecedented modification of the venerable Horner–Wadsworth–Emmons reaction, employing 2-fluoroethoxyphosphonates that may prove to be of general value in organic synthesis. These studies resulted in the discovery of some of the most potent epothilones reported to date. Equipped with functional groups to accommodate modern drug delivery technologies, some of these compounds exhibited picomolar potencies that qualify them as payloads for antibody drug conjugates (ADCs), while a number of them revealed impressive activities against drug resistant human cancer cells, making them desirable for potential medical applications

Improved Total Synthesis of Tubulysins and Design, Synthesis, and Biological Evaluation of New Tubulysins with Highly Potent Cytotoxicities against Cancer Cells as Potential Payloads for Antibody–Drug Conjugates

Improved, streamlined total syntheses of natural tubulysins such as V (<b>Tb45</b>) and U (<b>Tb46</b>) and pretubulysin D (<b>PTb-D43</b>), and their application to the synthesis of designed tubulysin analogues (<b>Tb44</b>, <b>PTb-D42</b>, <b>PTb-D47</b>–<b>PTb-D49</b>, and <b>Tb50</b>–<b>Tb120</b>), are described. Cytotoxicity evaluation of the synthesized compounds against certain cancer cell lines revealed a number of novel analogues with exceptional potencies [e.g., <b>Tb111</b>: IC₅₀ = 40 pM against MES SA (uterine sarcoma) cell line; IC₅₀ = 6 pM against HEK 293T (human embryonic kidney cancer) cell line; and IC₅₀ = 1.54 nM against MES SA DX (MES SA with marked multidrug resistance) cell line]. These studies led to a set of valuable structure–activity relationships that provide guidance to further molecular design, synthesis, and biological evaluation studies. The extremely potent cytotoxic compounds discovered in these investigations are highly desirable as potential payloads for antibody–drug conjugates and other drug delivery systems for personalized targeted cancer chemotherapies

Total Synthesis and Biological Evaluation of Natural and Designed Tubulysins

A streamlined total synthesis of <i>N</i>¹⁴-desacetoxytubulysin H (<b>Tb1</b>) based on a C–H activation strategy and a short total synthesis of pretubulysin D (<b>PTb-D43</b>) are described. Applications of the developed synthetic strategies and technologies to the synthesis of a series of tubulysin analogues (<b>Tb2</b>–<b>Tb41</b> and <b>PTb-D42</b>) are also reported. Biological evaluation of the synthesized compounds against an array of cancer cells revealed a number of novel analogues (e.g., <b>Tb14</b>), some with exceptional potencies against certain cell lines [e.g., <b>Tb32</b> with IC₅₀ = 12 pM against MES SA (uterine sarcoma) cell line and 2 pM against HEK 293T (human embryonic kidney) cell line], and a set of valuable structure–activity relationships. The highly potent cytotoxic compounds discovered in this study are highly desirable as payloads for antibody–drug conjugates and other drug delivery systems for personalized targeted cancer chemotherapies