N-(2-(2-(2-(4-(6-(6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)piperazin-1-yl)ethoxy)ethoxy)ethyl)-2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylamino)acetamide

ID: ALA4636355

PubChem CID: 132020568

Max Phase: Preclinical

Molecular Formula: C45H53N11O9

Molecular Weight: 891.99

Molecule Type: Unknown

Names and Identifiers

Canonical SMILES:  CC(=O)c1c(C)c2cnc(Nc3ccc(N4CCN(CCOCCOCCNC(=O)CNc5cccc6c5C(=O)N(C5CCC(=O)NC5=O)C6=O)CC4)cn3)nc2n(C2CCCC2)c1=O

Standard InChI:  InChI=1S/C45H53N11O9/c1-27-32-25-49-45(52-40(32)55(29-6-3-4-7-29)43(62)38(27)28(2)57)50-35-12-10-30(24-48-35)54-17-15-53(16-18-54)19-21-65-23-22-64-20-14-46-37(59)26-47-33-9-5-8-31-39(33)44(63)56(42(31)61)34-11-13-36(58)51-41(34)60/h5,8-10,12,24-25,29,34,47H,3-4,6-7,11,13-23,26H2,1-2H3,(H,46,59)(H,51,58,60)(H,48,49,50,52)

Standard InChI Key:  JWNZXWGMBRXMPK-UHFFFAOYSA-N

Molfile:  

 
     RDKit          2D

 65 72  0  0  0  0  0  0  0  0999 V2000
   42.8342  -25.8163    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   42.1246  -26.2340    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   26.4109  -23.7532    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   26.4109  -24.5808    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   27.1258  -24.9926    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   27.1258  -23.3373    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   27.8407  -23.7532    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   27.8391  -24.5790    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   28.5530  -24.9936    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   29.2689  -24.5793    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   29.2664  -23.7504    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   28.5521  -23.3436    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   27.1226  -22.5120    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   27.7929  -22.0238    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   27.5384  -21.2364    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   26.7107  -21.2364    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   26.4521  -22.0238    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   29.9826  -23.3364    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   30.6970  -23.7458    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   30.6947  -24.5736    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   31.4125  -24.9872    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   32.1296  -24.5689    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   32.1243  -23.7369    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   31.4059  -23.3313    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   32.8449  -24.9800    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   32.8466  -25.8087    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   33.5617  -26.2171    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   34.2796  -25.8056    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   34.2779  -24.9770    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   33.5581  -24.5598    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   27.1270  -25.8203    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   25.6924  -23.3435    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   25.6942  -24.9978    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   24.9762  -24.5830    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   25.6953  -25.8255    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   34.9926  -26.2177    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   35.7059  -25.8064    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   36.4189  -26.2184    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   37.1324  -25.8071    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   37.8454  -26.2192    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   38.5588  -25.8078    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   39.2718  -26.2199    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   39.9851  -25.8086    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   40.6981  -26.2206    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   41.4115  -25.8093    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   41.4173  -24.9857    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   43.5508  -26.2221    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   43.5551  -27.0442    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   44.2708  -27.4499    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   44.9815  -27.0321    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   44.2557  -25.8024    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   44.9701  -26.2016    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   45.5706  -25.6454    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   45.2271  -24.9025    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   44.4146  -24.9997    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   45.6266  -24.1862    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   46.4510  -24.1765    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   46.8527  -23.4617    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   46.4344  -22.7520    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   45.6100  -22.7617    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   45.2038  -23.4811    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   44.3804  -23.4919    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   46.8387  -22.0346    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   43.8550  -24.3954    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   46.3784  -25.8053    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
  1  2  1  0
  3  4  1  0
  3  6  1  0
  4  5  2  0
  5  8  1  0
  7  6  1  0
  7  8  2  0
  8  9  1  0
  9 10  2  0
 10 11  1  0
 11 12  2  0
 12  7  1  0
 13 14  1  0
 14 15  1  0
 15 16  1  0
 16 17  1  0
 17 13  1  0
  6 13  1  0
 11 18  1  0
 18 19  1  0
 19 20  2  0
 20 21  1  0
 21 22  2  0
 22 23  1  0
 23 24  2  0
 24 19  1  0
 25 26  1  0
 25 30  1  0
 26 27  1  0
 27 28  1  0
 28 29  1  0
 29 30  1  0
 22 25  1  0
  5 31  1  0
  3 32  2  0
  4 33  1  0
 33 34  1  0
 33 35  2  0
 28 36  1  0
 36 37  1  0
 37 38  1  0
 38 39  1  0
 39 40  1  0
 40 41  1  0
 41 42  1  0
 42 43  1  0
 43 44  1  0
 44 45  1  0
 45  2  1  0
 45 46  2  0
  1 47  1  0
 47 48  2  0
 48 49  1  0
 49 50  2  0
 50 52  1  0
 51 47  1  0
 51 52  2  0
 52 53  1  0
 53 54  1  0
 54 55  1  0
 55 51  1  0
 56 57  1  0
 56 61  1  0
 57 58  1  0
 58 59  1  0
 59 60  1  0
 60 61  1  0
 54 56  1  0
 61 62  2  0
 59 63  2  0
 55 64  2  0
 53 65  2  0
M  END

Alternative Forms

1. Parent:

   

   ALA4636355

   ---

Molecule Features

Natural Product: No

Oral: No

Chemical Probe: No

Parenteral: No

Molecule Type: Unknown

Topical: No

First In Class: No

Black Box: No

Chirality: No

Availability: No

Prodrug: No

Calculated Properties

Molecular Weight: 891.99

Molecular Weight (Monoisotopic): 891.4028

AlogP: 2.34

#Rotatable Bonds: 18

Polar Surface Area: 239.39

Molecular Species: NEUTRAL

HBA: 17

HBD: 4

#RO5 Violations: 2

HBA (Lipinski): 20

HBD (Lipinski): 4

#RO5 Violations (Lipinski): 2

CX Acidic pKa: 11.14

CX Basic pKa: 7.38

CX LogP: 1.92

CX LogD: 1.63

Aromatic Rings: 4

Heavy Atoms: 65

QED Weighted: 0.06

Np Likeness Score: -1.15

References

1. Anderson NA, Cryan J, Ahmed A, Dai H, McGonagle GA, Rozier C, Benowitz AB..  (2020)  Selective CDK6 degradation mediated by cereblon, VHL, and novel IAP-recruiting PROTACs.,  30  (9): [PMID:32184044] [10.1016/j.bmcl.2020.127106]

2. Gray, N S NS and 12 more authors.  1998-07-24  Exploiting chemical libraries, structure, and genomics in the search for kinase inhibitors.  [PMID:9677190]

3. Kubo, A A and 9 more authors.  1999-12  The p16 status of tumor cell lines identifies small molecule inhibitors specific for cyclin-dependent kinase 4.  [PMID:10632371]

4. Soni, R R and 7 more authors.  2000-09-07  Inhibition of cyclin-dependent kinase 4 (Cdk4) by fascaplysin, a marine natural product.  [PMID:10973815]

5. Lane, M E ME and 9 more authors.  2001-08-15  A novel cdk2-selective inhibitor, SU9516, induces apoptosis in colon carcinoma cells.  [PMID:11507069]

6. Tavares, Francis X FX and 7 more authors.  2004-09-09  N-Phenyl-4-pyrazolo[1,5-b]pyridazin-3-ylpyrimidin-2-amines as potent and selective inhibitors of glycogen synthase kinase 3 with good cellular efficacy.  [PMID:15341487]

7. Fry, David W DW and 10 more authors.  2004-11  Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts.  [PMID:15542782]

8. Pennati, Marzia M and 12 more authors.  2005-09  Potentiation of paclitaxel-induced apoptosis by the novel cyclin-dependent kinase inhibitor NU6140: a possible role for survivin down-regulation.  [PMID:16170024]

9. Sridhar, Jayalakshmi J, Akula, Nagaraju N and Pattabiraman, Nagarajan N.  2006-03-24  Selectivity and potency of cyclin-dependent kinase inhibitors.  [PMID:16584130]

10. DePinto, Wanda W and 19 more authors.  2006-11  In vitro and in vivo activity of R547: a potent and selective cyclin-dependent kinase inhibitor currently in phase I clinical trials.  [PMID:17121911]

11. Joshi, Kalpana S KS and 7 more authors.  2007-03  In vitro antitumor properties of a novel cyclin-dependent kinase inhibitor, P276-00.  [PMID:17363486]

12. Squires, Matthew S MS and 7 more authors.  2009-02  Biological characterization of AT7519, a small-molecule inhibitor of cyclin-dependent kinases, in human tumor cell lines.  [PMID:19174555]

13. Cirstea, D D and 15 more authors.  2013-12  Small-molecule multi-targeted kinase inhibitor RGB-286638 triggers P53-dependent and -independent anti-multiple myeloma activity through inhibition of transcriptional CDKs.  [PMID:23807770]

14. Gelbert, Lawrence M LM and 16 more authors.  2014-10  Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine.  [PMID:24919854]

15. Paiva, Cody C and 8 more authors.  2015  Cyclin-Dependent Kinase Inhibitor P1446A Induces Apoptosis in a JNK/p38 MAPK-Dependent Manner in Chronic Lymphocytic Leukemia B-Cells.  [PMID:26606677]

16. Bisi, John E JE, Sorrentino, Jessica A JA, Roberts, Patrick J PJ, Tavares, Francis X FX and Strum, Jay C JC.  2016-05  Preclinical Characterization of G1T28: A Novel CDK4/6 Inhibitor for Reduction of Chemotherapy-Induced Myelosuppression.  [PMID:26826116]

17. Klaeger, Susan S and 47 more authors.  2017-12-01  The target landscape of clinical kinase drugs.  [PMID:29191878]

18. Wang, Yan Y and 10 more authors.  2018-03-01  Design and synthesis of 4-(2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)-N-(5-(piperazin-1-ylmethyl)pyridine-2-yl)pyrimidin-2-amine as a highly potent and selective cyclin-dependent kinases 4 and 6 inhibitors and the discovery of structure-activity relationships.  [PMID:29429832]

19. Tear, Westley F and 16 more authors.  2020-01-23  Selectivity and Physicochemical Optimization of Repurposed Pyrazolo[1,5-b]pyridazines for the Treatment of Human African Trypanosomiasis.  [PMID:31846577]

20. Wu, Tizhi and 6 more authors.  2020-11-25  Recent Developments in the Biology and Medicinal Chemistry of CDK9 Inhibitors: An Update.  [PMID:32866383]

Source

Source(1):

• Scientific Literature