Details of the Drug

General Information of Drug (ID: DMYRBO1)

• Drug Name: Umbralisib
• Synonyms: RP5264; TGR-1202

Indication

Disease Entry	ICD 11	Status	REF
Follicular lymphoma	2A80	Approved	[1]
Marginal zone lymphoma	2A85.0	Approved	[1]
Diffuse large B-cell lymphoma	2A81	Phase 2/3	[2]
Chronic lymphocytic leukaemia	2A82.0	Phase 2	[3]
Non-hodgkin lymphoma	2B33.5	Phase 2	[3]

• #Ro5 Violations (Lipinski): 2:
  Molecular Weight (mw); 571.5
  Topological Polar Surface Area (xlogp); 5.8
  Rotatable Bond Count (rotbonds); 6
  Hydrogen Bond Donor Count (hbonddonor); 1
  Hydrogen Bond Acceptor Count (hbondacc); 10
• ADMET Property:
  Absorption Tmax: The time to maximum plasma concentration (Tmax) is 4 h [4]
  Clearance: The clearance of drug is 15.5 L/h [5]
  Elimination: During pharmacokinetic studies, about 81% of the umbralisib dose was recovered in feces (17% unchanged) [5]
  Half-life: The concentration or amount of drug in body reduced by one-half in 91 hours [5]
  Metabolism: The drug is metabolized via the CYP2C9, CYP3A4, and CYP1A2 enzymes [5]
  Vd: The volume of distribution (Vd) of drug is 312 L [5]
• Chemical Identifiers:
  Formula: C31H24F3N5O3
  IUPAC Name: 2-[(1S)-1-[4-amino-3-(3-fluoro-4-propan-2-yloxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]ethyl]-6-fluoro-3-(3-fluorophenyl)chromen-4-one
  Canonical SMILES: C[C@@H](C1=C(C(=O)C2=C(O1)C=CC(=C2)F)C3=CC(=CC=C3)F)N4C5=NC=NC(=C5C(=N4)C6=CC(=C(C=C6)OC(C)C)F)N
  InChI: InChI=1S/C31H24F3N5O3/c1-15(2)41-24-9-7-18(12-22(24)34)27-26-30(35)36-14-37-31(26)39(38-27)16(3)29-25(17-5-4-6-19(32)11-17)28(40)21-13-20(33)8-10-23(21)42-29/h4-16H,1-3H3,(H2,35,36,37)/t16-/m0/s1
  InChIKey: IUVCFHHAEHNCFT-INIZCTEOSA-N
• Cross-matching ID:
  PubChem CID: 72950888
  CAS Number: 1532533-67-7
  DrugBank ID: DB14989
  TTD ID: D0O8SJ

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Casein kinase I epsilon (CSNK1E)	TTA8PLI	KC1E_HUMAN	Inhibitor	[1]
PI3-kinase delta (PIK3CD)	TTGBPJE	PK3CD_HUMAN	Inhibitor	[1]

Molecular Expression Atlas of This Drug

• The Studied Disease: Follicular lymphoma
• ICD Disease Classification: 2A80

Molecule Name	Molecule Type	Gene Name	p-value	Fold-Change	Z-score
PI3-kinase delta (PIK3CD)	DTT	PIK3CD	4.31E-16	-0.37	-0.91

References

• [1] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2021
• [2] ClinicalTrials.gov (NCT02793583) Study to Assess the Efficacy and Safety of Ublituximab + Umbralisib With or Without Bendamustine and Umbralisib Alone in Patients With Previously Treated Non-Hodgkins Lymphoma (UNITY-NHL). U.S. National Institutes of Health.
• [3] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [4] Burris HA 3rd, Flinn IW, Patel MR, Fenske TS, Deng C, Brander DM, Gutierrez M, Essell JH, Kuhn JG, Miskin HP, Sportelli P, Weiss MS, Vakkalanka S, Savona MR, O'Connor OA: Umbralisib, a novel PI3Kdelta and casein kinase-1epsilon inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: an open-label, phase 1, dose-escalation, first-in-human study. Lancet Oncol. 2018 Apr;19(4):486-496. doi: 10.1016/S1470-2045(18)30082-2. Epub 2018 Feb 20.
• [5] FDA Approved Drug Products: UKONIQ (umbralisib) tablets, for oral use
• [6] 2017 FDA drug approvals.Nat Rev Drug Discov. 2018 Feb;17(2):81-85.
• [7] 2014 FDA drug approvals. Nat Rev Drug Discov. 2015 Feb;14(2):77-81.
• [8] PI3K-delta and PI3K-gamma inhibition by IPI-145 abrogates immune responses and suppresses activity in autoimmune and inflammatory disease models. Chem Biol. 2013 Nov 21;20(11):1364-74.
• [9] Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009 Aug;8(8):627-44.
• [10] Effective "activated PI3K syndrome"-targeted therapy with the PI3K inhibitor leniolisib. Blood. 2017 Nov 23;130(21):2307-2316.
• [11] Parsaclisib, a potent and highly selective PI3K inhibitor, in patients with relapsed or refractory B-cell malignancies. Blood. 2019 Apr 18;133(16):1742-1752.
• [12] The selective class I PI3K inhibitor CH5132799 targets human cancers harboring oncogenic PIK3CA mutations. Clin Cancer Res. 2011 May 15;17(10):3272-81.
• [13] INCB40093 is a selective PI3Kdelta inhibitor with potent antiproliferative activity against human B-cell tumors.
• [14] Crystal structure of a conformation-selective casein kinase-1 inhibitor. J Biol Chem. 2000 Jun 30;275(26):20052-60.
• [15] Selective inhibition of casein kinase 1 epsilon minimally alters circadian clock period. J Pharmacol Exp Ther. 2009 Aug;330(2):430-9.
• [16] Casein kinase 1 is a therapeutic target in chronic lymphocytic leukemia. Blood. 2018 Mar 15;131(11):1206-1218.