AZD5991 free acid | CAS#2143010-83-5 | Mcl-1 inhibitor

MedKoo Cat#: 206924 | Name: AZD5991 free acid

Description:

WARNING: This product is for research use only, not for human or veterinary use.

AZD5991 is a potent and selective Mcl-1 inhibitor for treatment of hematologic cancers. AZD5991 is a rationally designed macrocycle with sub-nanomolar affinity for Mcl-1. AZD5991 is an inhibitor of induced myeloid leukemia cell differentiation protein (myeloid cell leukemia-1; Mcl-1; Bcl2-L-3), with potential pro-apoptotic and antineoplastic activities. Upon administration, AZD5991 binds to Mcl-1, thereby preventing the binding of Mcl-1 to and inactivation of certain pro-apoptotic proteins, and promoting apoptosis of cells overexpressing Mcl-1.

Chemical Structure

AZD5991 free acid

CAS#2143061-81-6 (free acid)

Theoretical Analysis

MedKoo Cat#: 206924

Name: AZD5991 free acid

CAS#: 2143061-81-6 (free acid)

Chemical Formula: C35H34ClN5O3S2

Exact Mass: 671.1792

Molecular Weight: 672.26

Elemental Analysis: C, 62.53; H, 5.10; Cl, 5.27; N, 10.42; O, 7.14; S, 9.54

Price and Availability

Size	Price	Availability	Quantity
5mg	USD 550.00	2 Weeks
10mg	USD 950.00	2 Weeks

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Related CAS #

2143061-81-6 (free acid) 2143061-85-0 (sodium) 2143061-82-7 2143010-83-5

Synonym

AZD5991; AZD-5991; AZD 5991; AZD5991 free acid;

IUPAC/Chemical Name

(Z)-16-chloro-11,21,25,61-tetramethyl-11H,21H,61H-10-oxa-4,8-dithia-1(7,3)-indola-2(4,3),6(3,5)-dipyrazola-9(3,1)-naphthalenacyclotridecaphane-12-carboxylic acid

InChi Key

KBQCEQAXHPIRTF-UHFFFAOYSA-N

InChi Code

InChI=1S/C35H34ClN5O3S2/c1-20-31-29(38-40(20)3)19-45-17-22-15-23(41(4)37-22)18-46-24-14-21-8-5-6-9-25(21)30(16-24)44-13-7-10-26-27-11-12-28(36)32(31)33(27)39(2)34(26)35(42)43/h5-6,8-9,11-12,14-16H,7,10,13,17-19H2,1-4H3,(H,42,43)

SMILES Code

CN1C(C(O)=O)=C(CCCOC2=C(C=CC=C3)C3=CC(SC4)=C2)C5=CC=C(Cl)C(C6=C(C)N(C)N=C6CSCC7=NN(C)C4=C7)=C51

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO

Shelf Life

>2 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

AZD5991 is an inhibitor of induced myeloid leukemia cell differentiation protein (myeloid cell leukemia-1; Mcl-1; Bcl2-L-3), with potential pro-apoptotic and antineoplastic activities. Upon administration, AZD5991 binds to Mcl-1, thereby preventing the binding of Mcl-1 to and inactivation of certain pro-apoptotic proteins, and promoting apoptosis of cells overexpressing Mcl-1. Mcl-1, an anti-apoptotic protein belonging to the Bcl-2 family of proteins, is upregulated in cancer cells and promotes tumor cell survival. Mcl-1, a member of the Bcl/Mcl family, is a key protein involved in evasion of apoptosis in a wide variety of tumors. Its amplification and overexpression have also been implicated in innate and acquired resistance to anticancer drugs. Mcl-1 is capable of preventing induction of apoptosis, both by binding and inactivating the pro-apoptotic executioner Bcl-2 protein, Bak, as well as by sequestering other pro-apoptotic BH3-only proteins such as Bim and Noxa.

Product Data

Product Data

Instruction

View handling instruction

Biological target:

AZD-5991 is a potent and selective Mcl-1 inhibitor with an IC50 of 0.7 nM in FRET assay.

In vitro activity:

Treatment with AZD5591 diminished proliferation of DLBCL cells in a dose-dependent manner. Activated B-cell (ABC)-like cell lines OCI-LY10 and OCI-LY3 and germinal center B-cell (GCB)-like cell lines VAL, SU-DHL4 and SU-DHL6 were most sensitive to the drug (Fig. 1A). Meanwhile, other GCB (SU-DHL10, OCI-LY18) and ABC DLBCL cells (U-2932) showed resistance. Both parental and ibrutinib-resistant MCL cells were highly susceptible to Mcl-1 inhibition (IC50~0.3 μM; Fig. 1B). Reference: Clin Cancer Res. 2021 Jul 7:clincanres.0464.2021. https://pubmed.ncbi.nlm.nih.gov/34233959/

In vivo activity:

Ten days after treatment, AZD5991 showed 52% and 93% TGI (p < 0.0001) at 10 and 30 mg kg−1, respectively. At the same time point, AZD5991 at 60 mg kg−1 led to 99% TR with no detectable tumors in 6 out of 7 mice, while complete TR was seen in 7 out of 7 mice in the 100 mg kg−1 dose group. AZD5991 also showed a dose-dependent duration of response with tumors in the 100 mg kg−1 group growing back later than those in the 60 mg kg−1 group. Reference: Nat Commun. 2018; 9: 5341. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6297231/

	Solvent	mg/mL	mM
Solubility
	DMSO, sonicated	25.0	37.19

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 672.26 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. Liu T, Lam V, Thieme E, Sun D, Wang X, Xu F, Wang L, Danilova OV, Xia Z, Tyner JW, Kurtz SE, Danilov AV. Pharmacologic targeting of Mcl-1 induces mitochondrial dysfunction and apoptosis in B-cell lymphoma cells in a TP53- and BAX-dependent manner. Clin Cancer Res. 2021 Jul 7:clincanres.0464.2021. doi: 10.1158/1078-0432.CCR-21-0464. Epub ahead of print. PMID: 34233959. 2. Tron AE, Belmonte MA, Adam A, Aquila BM, Boise LH, Chiarparin E, Cidado J, Embrey KJ, Gangl E, Gibbons FD, Gregory GP, Hargreaves D, Hendricks JA, Johannes JW, Johnstone RW, Kazmirski SL, Kettle JG, Lamb ML, Matulis SM, Nooka AK, Packer MJ, Peng B, Rawlins PB, Robbins DW, Schuller AG, Su N, Yang W, Ye Q, Zheng X, Secrist JP, Clark EA, Wilson DM, Fawell SE, Hird AW. Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia. Nat Commun. 2018 Dec 17;9(1):5341. doi: 10.1038/s41467-018-07551-w. PMID: 30559424; PMCID: PMC6297231.

In vitro protocol:

In vivo protocol:

1: Desai P, Lonial S, Cashen A, Kamdar M, Flinn I, O'Brien S, Garcia JS, Korde N, Moslehi J, Wey M, Cheung P, Sharma S, Olabode D, Chen H, Ali Syed F, Liu M, Saeh J, Andrade-Campos M, Kadia TM, Blachly JS. A Phase 1 First-in-Human Study of the MCL-1 Inhibitor AZD5991 in Patients with Relapsed/Refractory Hematologic Malignancies. Clin Cancer Res. 2024 Nov 1;30(21):4844-4855. doi: 10.1158/1078-0432.CCR-24-0028. PMID: 39167622; PMCID: PMC11528199. 2: White MJ, Cheatham L, Wen S, Scarfe G, Cidado J, Reimer C, Hariparsad N, Jones RDO, Drew L, McGinnity DF, Vasalou C. A PKPD Case Study: Achieving Clinically Relevant Exposures of AZD5991 in Oncology Mouse Models. AAPS J. 2023 Jun 28;25(4):66. doi: 10.1208/s12248-023-00836-z. PMID: 37380821. 3: Zhang H, Nakauchi Y, Köhnke T, Stafford M, Bottomly D, Thomas R, Wilmot B, McWeeney SK, Majeti R, Tyner JW. Integrated analysis of patient samples identifies biomarkers for venetoclax efficacy and combination strategies in acute myeloid leukemia. Nat Cancer. 2020 Aug;1(8):826-839. doi: 10.1038/s43018-020-0103-x. Epub 2020 Aug 18. PMID: 33123685; PMCID: PMC7591155. 4: Liu S, Qiao X, Wu S, Gai Y, Su Y, Edwards H, Wang Y, Lin H, Taub JW, Wang G, Ge Y. c-Myc plays a critical role in the antileukemic activity of the Mcl-1-selective inhibitor AZD5991 in acute myeloid leukemia. Apoptosis. 2022 Dec;27(11-12):913-928. doi: 10.1007/s10495-022-01756-7. Epub 2022 Aug 9. PMID: 35943677. 5: Yang W, Cook S, Wu D. Pre-clinical Formulation Development of an in situ Meglumine Salt of AZD5991: A Novel Macrocyclic Mcl-1 Inhibitor. Pharm Res. 2023 Apr;40(4):977-988. doi: 10.1007/s11095-023-03503-2. Epub 2023 Apr 3. PMID: 37012536. 6: Wang Y, Wang D, Wang Y, Yang H, Wang G, Wu S. Synergistic activity and mechanism of cytarabine and MCL-1 inhibitor AZD5991 against acute myeloid leukemia. Neoplasma. 2023 Apr;70(2):287-293. doi: 10.4149/neo_2023_221217N1185. Epub 2023 Feb 23. PMID: 36812234. 7: Tron AE, Belmonte MA, Adam A, Aquila BM, Boise LH, Chiarparin E, Cidado J, Embrey KJ, Gangl E, Gibbons FD, Gregory GP, Hargreaves D, Hendricks JA, Johannes JW, Johnstone RW, Kazmirski SL, Kettle JG, Lamb ML, Matulis SM, Nooka AK, Packer MJ, Peng B, Rawlins PB, Robbins DW, Schuller AG, Su N, Yang W, Ye Q, Zheng X, Secrist JP, Clark EA, Wilson DM, Fawell SE, Hird AW. Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia. Nat Commun. 2018 Dec 17;9(1):5341. doi: 10.1038/s41467-018-07551-w. PMID: 30559424; PMCID: PMC6297231. 8: Li Y, Lee HH, Jiang VC, Che Y, McIntosh J, Jordan A, Vargas J, Zhang T, Yan F, Simmons ME, Wang W, Nie L, Yao Y, Jain P, Wang M, Liu Y. Potentiation of apoptosis in drug-resistant mantle cell lymphoma cells by MCL-1 inhibitor involves downregulation of inhibitor of apoptosis proteins. Cell Death Dis. 2023 Nov 2;14(11):714. doi: 10.1038/s41419-023-06233-w. PMID: 37919300; PMCID: PMC10622549. 9: Goliaei A, Woods HA, Tron AE, Belmonte MA, Secrist JP, Ferguson D, Drew L, Fretland AJ, Aldridge BB, Gibbons FD. Multiscale Model Identifies Improved Schedule for Treatment of Acute Myeloid Leukemia In Vitro With the Mcl-1 Inhibitor AZD5991. CPT Pharmacometrics Syst Pharmacol. 2020 Oct;9(10):561-570. doi: 10.1002/psp4.12552. Epub 2020 Sep 17. PMID: 32860732; PMCID: PMC7577016. 10: Balazs AYS, Carbajo RJ, Davies NL, Dong Y, Hird AW, Johannes JW, Lamb ML, McCoull W, Raubo P, Robb GR, Packer MJ, Chiarparin E. Correction to "Free Ligand 1D NMR Conformational Signatures To Enhance Structure Based Drug Design of a Mcl-1 Inhibitor (AZD5991) and Other Synthetic Macrocycles". J Med Chem. 2021 Mar 11;64(5):2849. doi: 10.1021/acs.jmedchem.1c00273. Epub 2021 Mar 1. Erratum for: J Med Chem. 2019 Nov 14;62(21):9418-9437. doi: 10.1021/acs.jmedchem.9b00716. PMID: 33646774.